CN105980386A - Pyrazolo compounds and uses thereof - Google Patents

Abstract

Provided are compounds useful as inhibitors of one or more histone demethylses, such as KDM5. The invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using the present composition in the treatment of various disorders.

Description

Pyrazolo compounds and application thereof

Invention field

The present invention relates to be useful as the compound of histone demethylase inhibitors.

Background of invention

The nucleotide of 3,000,000,000 human genomes is packaged in nucleus and needs huge compacting.In order to realize this mesh , the DNA in our chromosome is wrapped in around the protein bobbin of referred to as histone, is referred to as chromatinic cause to be formed The protein of close repetition/DNA polymer: the template limited for gene regulation.It is far from and is used only as packing module, chromatin mould Plate is formed and obtains new understanding and the basis of the vital one group of mechanisms of gene regulation being referred to as epigenetic regulation.By composing Giving histone and the various specified chemical of DNA to modify, epigenetic regulator adjusts the structure of genome, function and can Access property, thus gene expression is played tremendous influence.The most having identified hundreds of epigenetic-effect devices, many of which is Chromatin knot synthase or chromatin modification enzyme.It should be noted that these enzymes increasing are the most neural with various diseases Neuodegenerative disorder, metabolic disease, inflammation and cancer are associated.Therefore, the therapeutic agent for this kind of emerging gene regulation enzyme carries Supply to treat the new method of human diseases.

Additionally, the Drug resistance to cancer therapy drug of relatively rapid acquisition remains the successful major obstacle for the treatment of of cancer.Explain The making great efforts in a large number of bright this drug-fast molecular basis has revealed that various mechanism, including the medicine of drug efflux, target combine- The acquisition of deficient mutants, the joint substituting surviving path and epigenetic change.Swelling during Drug therapy Oncocyte group has been found that rare, random, to give resistance heredity change.See Sharma etc., Cell 141 (1): 69-80(2010).Find that the KDM5/JARID1 family of histone demethylase can play cancer resistance effect.Mankind's demethylase KDM5/JARID1 family comprise four members: KDM5A, KDM5B, KDM5C and KDM5D.KDM5 family member comprises five guarantors Keep domain: JmjN, ARID, JmjC, PHD and C₅HC₂Zinc refers to.The aminoacid sequence of KDM5A, KDM5B, KDM5C and KDM5D is Known and can openly obtain, for example, with reference to UniProtKB/Swiss-Prot, (see for example, KDM5A is (such as, P29375-1 and P29375-2), KDM5B (such as, Q9UGL1-1 and Q9UGL1-2), KDM5C (such as, P41229-1, P41229-2, P41229-3 and P41229-4) and KDM5D (such as, Q9BY66-1, Q9BY66-2 and Q9BY66-3).At present Needs be used for treating excess proliferative disease, prevent Drug resistance and/or for improve other treatments of cancer (such as, targeted therapy, Chemotherapy and radiotherapy) compound of suppression KDM5 demethylase of effect.

Summary of the invention

It has now been discovered that the compound of the present invention and pharmaceutically acceptable compositions thereof can be effectively as histone piptonychias The inhibitor of base, it includes 2-oxoglutaric acid dependent enzyme such as the protein containing Jumonji domain, the H3K4 of protein The JARID subtribe member of (H3 K4) demethylase family member and/or histone demethylase.This compounds has Formulas I:

Or its pharmaceutically acceptable salt, wherein R¹With ring A be as defined herein with describe.

The compound provided and pharmaceutically acceptable compositions thereof are applicable to treatment and pass through by histone demethylation Enzyme is (such as 2-oxoglutaric acid dependent form enzyme, the protein containing Jumonji domain, H3K4 (H3 K4) piptonychia of protein The JARID subtribe member of base enzyme family member and/or enzyme) various diseases that the abnormal cell reaction that caused of the event that mediates is relevant Disease, disease or condition of illness.These diseases, disease or condition of illness include described herein those.

The compound provided applies also for studying the histone demethylase in biology and pathological phenomena (such as 2-ketone 1,3-propanedicarboxylic acid dependent form enzyme, the protein containing Jumonji domain, H3K4 (H3 K4) the demethylase family of protein The JARID subtribe member of member and/or enzyme), research by these histone demethylases mediation intracellular signal transduction approach And the novel inhibitors of comparative these and other histone demethylases of evaluation.

On the other hand including compositions, it comprises formula (I) compound or its pharmaceutically acceptable salt and pharmaceutically may be used Adjuvant, carrier or the excipient accepted.

On the other hand the compound for treating disease, disease or the condition of illness relevant to KDM5 activity or compositions are included. These diseases, disease or situation include described herein those.

On the other hand formula (I) compound and salt thereof are included.

On the other hand the pharmaceutical composition containing formula (I) compound or its salt is included.

On the other hand the method including the disease that a kind for the treatment of is relevant to KDM5 activity, it includes executing to patient in need With formula (I) compound or its pharmaceutically acceptable salt of therapeutically effective amount.

On the other hand formula (I) compound or its pharmaceutically acceptable salt purposes in the treatment are included.The opposing party's bread Include the purposes in the treatment of the pharmaceutical composition containing formula (I) compound or its pharmaceutically acceptable salt.

On the other hand include that formula (I) compound or its pharmaceutically acceptable salt are treating the disease relevant to KDM5 activity In purposes.On the other hand include pharmaceutical composition containing formula (I) compound or its pharmaceutically acceptable salt treatment with Purposes in the disease that KDM5 activity is relevant.

On the other hand include that formula (I) compound or its pharmaceutically acceptable salt are manufacturing for treatment and KDM5 activity phase Purposes in the medicine of the disease closed.On the other hand include containing formula (I) compound or the medicine of its pharmaceutically acceptable salt Compositions purposes in manufacturing the medicine for treating the disease relevant to KDM5 activity.

On the other hand a kind of method including curative effect improving the treatment of cancer containing cancer therapeutic agent, it includes to patient Use the cancer therapeutic agent of formula (I) compound of (a) effective dose or its pharmaceutically acceptable salt and (b) effective dose.

On the other hand include that a kind for the treatment of suffers from the individual method of cancer, described individuality have increase to treatment of cancer Agent produces the probability of resistance, described method include to described individuality use formula (I) compound of (a) effective dose or its pharmaceutically Acceptable salt and the cancer therapeutic agent of (b) effective dose.

On the other hand include mediating by this class histone demethylase for seminar albumen demethylase such as KDM5, research Intracellular signal transduction approach and the compound of adjusting control agent of comparative these demethylases of evaluation.

On the other hand include a kind of for formula I or the method for its salt.

On the other hand a kind of newly synthesized centre being applicable to prepare formula (I) compound or its salt disclosed herein is included Body.

The detailed description of some embodiment

The general introduction of the compound of the present invention

In certain embodiments, the present invention provides a kind of compound of formula I:

Or its pharmaceutically acceptable salt, wherein:

R¹For R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、- C(O)C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O) R、-N(R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R′)₂,-C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；

Each R independently be hydrogen or the optionally substituted group selected from the following: C_1–6Aliphatic series, phenyl, 3-7 unit satisfy With or part unsaturated carbocyclic, 8-10 unit dicyclo are saturated, part is unsaturated or aromatic ring, have 1-3 independently selected from nitrogen, oxygen or The heteroatomic 5-6 unit bicyclic heteroaryl ring of sulfur, have 1-2 saturated independently selected from the heteroatomic 4-7 unit of nitrogen, oxygen or sulfur Or part unsaturated heterocycle, have that 1-4 is saturated independently selected from the heteroatomic 7-10 unit dicyclo of nitrogen, oxygen or sulfur or part the most not Saturated heterocyclic or there is 1-4 the heteroatomic 8-10 unit Bicyclic heteroaromatic rings independently selected from nitrogen, oxygen or sulfur；

Each R ' independently be R ,-C (O) R ,-CO₂R or two R ' on same nitrogen and the atom between them Formed together and there is 1-2 the heteroatomic 4-7 unit heterocycle independently selected from nitrogen, oxygen and sulfur；

Ring A is

R²And R³Independently be-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N (R′)₂、-C(O)SR、-C(O)C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N (R′)₂、-N(R′)C(O)R、-N(R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂、-N (R ') C (=N (R ')) N (R ')₂,-C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R′)₂；Or:

R²And R³Formed together with the atom between them and optionally substituted there is 0-4 independently selected from nitrogen, oxygen and sulfur Heteroatomic 5-7 unit part is unsaturated or aromatic condensed ring；

R^2′For R ,-OR ,-SR ,-N (R ')₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O)C(O)R、-C (O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N(R′)C(O)N (R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂,-C=NN (R′)₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R^2′And R³Formed together with the atom between them optionally substituted have 1-4 independently selected from nitrogen, oxygen and The heteroatomic 5-7 unit part unsaturation of sulfur or aromatic condensed ring；

X is N (R⁴)-,-O-or-S-；

R⁴For-R ,-C (O) R ,-CO₂R or-S (O)₂R；Or:

R⁴And R³Formed together with the atom between them and optionally substituted there is 1-4 independently selected from nitrogen, oxygen and sulfur Heteroatomic 5-7 unit saturated, part is unsaturated or aromatic condensed ring；

R⁵For R ,-C (O) R ,-CO₂R、-C(O)N(R′)₂,-C (O) C (O) R or-C (O) CH₂C(O)R；Or:

R⁵And R²Formed together with the atom between them and optionally substituted there is 1-4 independently selected from nitrogen, oxygen and sulfur Heteroatomic 5-7 unit part is unsaturated or aromatic condensed ring；And

R⁶For R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、- C(O)C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O) R、-N(R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R′)₂,-C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R⁶And R³Formed together with the atom between them and optionally substituted there is 0-4 independently selected from nitrogen, oxygen and sulfur Heteroatomic 5-7 unit part is unsaturated or aromatic condensed ring.

In some embodiments, the invention provides except following compound of formula I in addition to any one:

Compound and definition

Concrete functional group and being defined on of the technical terms of chemistry are described more particularly below.For the purposes, chemical element According to Handbook of Chemistry and Physics, the 75th edition, the CAS version periodic table of elements of interior front cover identifies also And specifically functional group generally defines as described therein.Additionally, vitochemical General Principle and concrete functional moiety It is described in Organic Chemistry, Thomas Sorrell, University Science Books with reactivity, Sausalito,1999；Smith and March March ' s Advanced Organic Chemistry, the 5th edition, John Wiley&Sons,Inc.,New York,2001；Larock,Comprehensive Organic Transformations, VCH Publishers,Inc.,New York,1989；Carruthers,Some Modern Methods of Organic Synthesis, the 3rd edition, Cambridge University Press, Cambridge, 1987；Every list of references whole Content is all incorporated by reference herein.

Unless otherwise noted, structures described herein also implies that all isomerss including described structure (such as, enantiomer, diastereomer and geometric isomer (or conformer)) form；Such as, each asymmetric R and the S configuration at center, the double bond isomer of Z and E and the conformer of Z and E.Therefore, the compounds of this invention is single vertical Body chemical isomer and enantiomer, diastereomer and geometric isomer (or conformer) mixture are also at this In the range of invention.Unless otherwise noted, all tautomeric forms of the compound of the present invention are also at the model of the present invention In enclosing.Additionally, unless otherwise noted, structure depicted herein also imply that include only rich at one or more isotopes Compound different in the presence of collection atom.Such as, there is present configuration and (include that hydrogen is replaced by deuterium or tritium or carbon is rich Contain¹³C-or¹⁴C-carbon displacement) compound also within the scope of the invention.Such as, this compound is useful as surveying biology Determine the analytical tool in method, probe or be used as the therapeutic agent according to the present invention.

In some embodiments, when the most specific enantiomer, described specific enantiomer can be big On body, the mode without corresponding enantiomer provides, and also is referred to alternatively as " optically enriched ".As used herein, " optics Enrichment " mean that described compound is made up of a kind of enantiomer of notable larger proportion.In certain embodiments, chemical combination Thing is made up of the preferred enantiomer of at least about 90 weight %.In other embodiments, compound is by least about 95 weights The preferred enantiomer composition of amount %, 98 weight % or 99 weight %.Preferably enantiomer can pass through people in the art The known any method of member separates from racemic mixture, and described method includes Chiral high pressure liquid chromatograph (HPLC) and hands Formation and the crystallization of property salt or prepared by asymmetric synthesis.See for example, Jacques etc., Enantiomers, Racemates and Resolutions(Wiley Interscience,New York,1981)；Wilen etc., Tetrahedron 33:2725(1977)；Eliel,E.L.Stereochemistry of Carbon Compounds (McGraw–Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical (E.L.Eliel writes Resolutions page 268, Univ.of Notre Dame Press, Notre Dame, IN 1972)。

Term " hetero atom " means that oxygen, sulfur, nitrogen, phosphorus or silicon (include any oxidised form of nitrogen, sulfur, phosphorus or silicon；Arbitrarily alkali The quaternization of property nitrogen；Or heterocycle may replace nitrogen, such as N (as 3, in 4-dihydro-2 h-pyrrole base), NH are (as pyrroles In alkyl) or NR⁺(as in the substituted pyrrolidinyl of N-)) in one or more.

As used herein, " direct key " or " covalent bond " refer to singly-bound, double or triple bonds.In some embodiment In, " direct key " or " covalent bond " refer to singly-bound.

As used herein, term " halo " and " halogen " refer to selected from fluorine (fluoro, F), chlorine (chloro, Cl), bromine (bromo, Br) and the atom of iodine (iodo, I).

As used herein, term " aliphatic series " or " aliphatic group " represent hydrocarbon part, and it can be straight chain (that is, non- Chain), side chain or ring-type (include condensing, bridging and spiral fused polycycle) and can be fully saturated or can containing one or Multiple unsaturated units, but described unit is not aromatic series.Except as otherwise noted, otherwise aliphatic group to contain 1-6 carbon former Son.In some embodiments, aliphatic group contains 1-4 carbon atom, and in other embodiments, aliphatic group contains 1- 3 carbon atoms.Suitably aliphatic group includes but not limited to, the alkyl of straight or branched, thiazolinyl and alkynyl, and its heterozygosis Thing, such as (cycloalkyl) alkyl, (cycloalkenyl group) alkyl or (cycloalkyl) thiazolinyl.

As used herein, term " unsaturated " means that a part has one or more unsaturated unit.

Alone or as major part a part use term " cyclic aliphatic ", " carbocyclic ring ", " carbocylic radical ", " carbocyclic ring is also " or " carbocyclic ring " refer to the most saturated or part undersaturated cyclic aliphatic monocycle or the ring system of dicyclo System, it has 3 to 10 members, and wherein said aliphatic ring systems is optionally taken with described herein as hereinbefore defined Generation.Cycloaliphatic groups includes but not limited to, cyclopropyl, cyclobutyl, cyclopenta, cyclopentenyl, cyclohexyl, cyclohexenyl group, cycloheptyl Base, cycloheptenyl, ring octyl group, cyclo-octene base and cyclo-octadiene base.In some embodiments, cycloalkyl has 36 carbon. Term " cyclic aliphatic ", " carbocyclic ring ", " carbocylic radical ", " carbocyclic ring is also " or " carbocyclic ring " also include being fused to one or more aromatic series Or the aliphatic ring of non-aromatic ring, such as decahydro naphthyl, tetralyl, decahydronaphthalenes or dicyclo also [2.2.2] octane, wherein connect Group or junction point are on aliphatic series ring.

As used herein, term " ring alkylidene " refers to divalent cycloalkyl.In certain embodiments, ring alkylidene It is 1,1-ring alkylidene (that is, spiral fused rings).Exemplary 1,1-ring alkylidene includesIn other embodiments In, ring alkylidene is 1,2-ring alkylidene or 1,3-ring alkylidene.Exemplary 1,2-ring alkylidene includes

As used herein, term " alkyl " refers to by removing single hydrogen atom by containing the carbon between one to six The derivative unit price of the aliphatic part of atom saturated, straight or branched alkyl.In some embodiments, alkyl comprises 1-5 Carbon atom.In another embodiment, alkyl comprises 1-4 carbon atom.In other embodiments, alkyl comprises 1-3 Carbon atom.And in another embodiment, alkyl comprises 1-2 carbon atom.The example of alkyl includes but not limited to methyl, second Base, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, sec-amyl, isopentyl, the tert-butyl group, n-pentyl, neopentyl, just oneself Base, Sec-Hexyl, n-heptyl, n-octyl, positive decyl, n-undecane base, dodecyl etc..

As used herein, term " thiazolinyl " represents double by having at least one carbon-to-carbon by removing single hydrogen atom The monoradical that the straight or branched aliphatic part of key is derivative.In certain embodiments, thiazolinyl contains 2-6 carbon atom.? In some embodiment, thiazolinyl contains 2-5 carbon atom.In some embodiments, thiazolinyl contains 2-4 carbon atom.Separately In some embodiments, thiazolinyl contains 2-3 carbon atom.Thiazolinyl include such as ethylidine (vinyl), acrylic (pi-allyl), Cyclobutenyl, 1-methyl-2-butene-1-base etc..

As used herein, term " alkynyl " refers to by removing single hydrogen atom by having at least one carbon-to-carbon three The monoradical that the straight or branched aliphatic part of key is derivative.In certain embodiments, alkynyl contains 2-6 carbon atom.? In some embodiment, alkynyl contains 2-5 carbon atom.In some embodiments, alkynyl contains 2-4 carbon atom.Separately In one embodiment, alkynyl contains 2-3 carbon atom.Representative alkynyl includes but not limited to, acetenyl, 2-propynyl (alkynes Propyl group), 1-propinyl etc..

A part alone or as greater part (such as " aralkyl ", " aralkoxy " or " aryloxy alkyl ") makes Term " aryl " refer to monocycle and the bicyclic system with five to ten ring memberses altogether, the most in systems at least one Ring be aromatics and wherein each ring in system contain three to seven ring memberses.Term " aryl " can be with term " aryl rings " Exchange and use.In certain embodiments of the invention, " aryl " refers to the aromatics ring system of the one or more substituent group of portability System, it includes but not limited to phenyl, biphenyl, naphthyl, anthryl etc..As used herein, also wrap in the range of term " aryl " Include wherein aromatic ring and be fused to the group of one or more non-aromatic ring, such as indanyl, phthalimide-based, naphthalimide Base, phenanthridinyl or tetralyl etc..

The art used alone or as a part for major part (such as " heteroarylalkyl " or " heteroaryl alkoxyl ") Language " heteroaryl " and " heteroaryl-" refer to have 5 to 10 annular atomses, preferably 5,6 or 9 annular atomses；In ring array share 6, 10 or 14 pi-electrons；And outside carbon atom, there is 1 to 5 heteroatomic group.Term " hetero atom " refer to nitrogen, oxygen or Sulfur, and include any oxidised form of nitrogen or sulfur, and any quaternization of basic nitrogen.Heteroaryl includes but does not limits In, thienyl, furyl, pyrrole radicals, imidazole radicals, pyrazolyl, triazolyl, tetrazole radical, oxazolyl, isoxazolyl, di azoly, Thiazolyl, isothiazolyl, thiadiazolyl group, pyridine radicals, pyridazinyl, pyrimidine radicals, pyrazinyl, indolizine base, purine radicals, naphthyridinyl and Pteridine radicals.As used herein, term " heteroaryl " and " heteroaryl-" also include that wherein heteroaromatic rings is fused to one or more virtue The group of base, cyclic aliphatic or heterocyclic ring, wherein linking group or junction point are on heteroaromatic rings.Limiting examples includes Indyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuran group, indazolyl, benzimidazolyl, benzothiazole Base, quinolyl, isoquinolyl, cinnolines base, phthalazinyl, quinazolyl, quinoxalinyl, 4H quinolizinyl, carbazyl, acridinyl, fen Piperazine base, phenothiazinyl, phenazinyl, tetrahydric quinoline group, tetrahydro isoquinolyl and pyrido [2,3-b]-1,4-piperazine-3 (4H)-one.Heteroaryl can be monocycle or dicyclo.Term " heteroaryl " can be with term " heteroaryl ring ", " heteroaryl group " or " heteroaryl Race " exchange use, arbitrarily these terms include optionally substituted ring.Term " heteroarylalkyl " refers to the alkane being substituted by heteroaryl Base, wherein said alkyl and heteroaryl moieties are optionally substituted independently.

As used herein, term " heterocycle (heterocycle) ", " heterocyclic radical ", " heterocyclic group " and " heterocycle (heterocyclic ring) " it is used interchangeably, and refer to saturated or part is undersaturated and has outside carbon atom One or more, preferably one to four heteroatomic 4 to 7 yuan of stable monocycles as defined above or 7 to 10 yuan of dicyclos Heterocyclic moiety.When the annular atoms relating to heterocycle uses, term " nitrogen " includes substituted nitrogen.For example, there is 0-3 In the heteroatomic saturated of oxygen, sulfur or nitrogen or the unsaturated ring of part, nitrogen can be N (as 3,4-dihydro-2 h-pyrrole base In), NH (as in pyrrolidinyl) or⁺NR (as in the substituted pyrrolidinyl of N-).

Heterocycle can be connected to its side base, and arbitrarily annular atoms at any heteroatom producing rock-steady structure or carbon atom Can be optionally substituted.This kind of saturated or part unsaturated heterocycle group example includes but not limited to, tetrahydrofuran base, tetrahydrochysene Thienyl, pyrrolidinyl, pyrrolidone-base, piperidyl, pyrrolinyl, tetrahydric quinoline group, tetrahydro isoquinolyl, decahydroquinoline Base, oxazolidinyl, piperazinyl, dialkyl group, dioxolanyl, diazaBase, oxygen azepineBase, sulfur azepineBase, morpholine Generation and quininuclidinyl.Term " heterocycle ", " heterocyclic radical (heterocyclyl) ", " heterocyclic ring ", " heterocyclic group ", " heterocycle Part " and " heterocyclic radical (heterocyclic radical) " use can be exchanged in this article, and also include wherein heterocyclic radical Ring is fused to one or more aryl, heteroaryl or the group of cyclic aliphatic ring, such as indolinyl, 3H-indyl, benzo dihydro Pyranose, phenanthridinyl, 2-azabicyclic [2.2.1] heptyl, octahydro indyl or tetrahydric quinoline group, wherein linking group or connection Point is on heterocyclic ring.Heterocyclic radical can be monocycle or dicyclo.Term " cycloheteroalkylalkyl " refers to the alkyl replaced by heterocyclic radical, Wherein said alkyl and heterocyclyl moieties are optionally substituted independently.

As used herein, term " part is undersaturated " refers to include at least one double bond or three between annular atoms Key but be not the loop section of aromatics.Term " part is unsaturated " is intended to contain the ring with multiple unsaturated sites, and is not intended to Including aryl as defined herein or heteroaryl moieties.

Term " alkylidene " refers to divalent alkyl." alkylidene chain " is polymethylene, i.e.-(CH₂)_n-, wherein n is the most whole Number, preferably 1 to 6,1 to 4,1 to 3,1 to 2 or 2 to 3.Substituted alkylidene chain is wherein one or more methylene hydrogen atoms It is replaced the polymethylene of base displacement.Suitably substituent group includes replacing below for those described by substituted aliphatic group Base.

As described in this article, the compound of the present invention can contain " optionally substituted " part.Generally, term " takes Generation ", no matter above with or without term " optionally ", all mean that one or more hydrogen of specified portions are replaced by suitable substituent group. Unless otherwise noted, otherwise " optionally substituted " group can may replace to have on position described group each and suitably take Dai Ji, and when the more than one substituent group that position more than one in any given structure can be selected from designated groups replaces, Described substituent group can be identical or different in each position.The combination of substituent group expected from the present invention preferably results in surely Those combinations fixed or chemical feasible compound.As used herein, term " stable " refers to allow them standing Produce, detection and allow them to reclaim in certain embodiments, purification for one or more purposes disclosed herein Condition time the compound that generally will not change.

Suitable monovalent substituent on the substitutable carbon atom of " optionally substituted " group independently be halogen；- (CH₂)₀-₄R^○；-(CH₂)₀-₄OR^○；-O-(CH₂)₀-₄C(O)OR^○；-(CH₂)₀-₄CH(OR^○)₂；-(CH₂)₀-₄SR^○；-(CH₂)₀-₄Ph, it can be by R^○Replace；-(CH₂)₀-₄O(CH₂)₀-₁Ph, it can be by R^○Replace；-CH=CHPh, it can be by R^○Replace；-NO₂；- CN；-N₃；-(CH₂)₀-₄N(R^○)₂；-(CH₂)₀-₄N(R^○)C(O)R^○；-N(R^○)C(S)R^○；-(CH₂)₀-₄N(R^○)C(O)NR^○ ₂；- N(R^○)C(S)NR^○ ₂；-(CH₂)₀-₄N(R^○)C(O)OR^○；-N(R^○)N(R^○)C(O)R^○；-N(R^○)N(R^○)C(O)NR^○ ₂；-N(R^○)N(R^○)C(O)OR^○；-(CH₂)₀-₄C(O)R^○；-C(S)R^○；-(CH₂)₀-₄C(O)OR^○；-(CH₂)₀-₄C(O)N(R^○)₂；- (CH₂)₀-₄C(O)SR^○；-(CH₂)₀-₄C(O)OSiR^○ ₃；-(CH₂)₀-₄OC(O)R^○；-OC(O)(CH₂)₀-₄SR-；SC(S)SR^○；- (CH₂)₀-₄SC(O)R^○；-(CH₂)₀-₄C(O)NR^○ ₂；-C(S)NR^○ ₂；-C(S)SR^○；-SC(S)SR^○；-(CH₂)₀-₄OC(O)NR^○ ₂；-C(O)N(OR^○)R^○；-C(O)C(O)R^○；-C(O)CH₂C(O)R^○；-C(NOR^○)R^○；-CH₂)₀-₄SSR^○；-(CH₂)₀–₄S (O)₂R^○；-(CH₂)₀-₄S(O)₂OR^○；-(CH₂)₀-₄OS(O)₂R^○；-S(O)₂NR^○ ₂；-(CH₂)₀-₄S(O)R^○；-N(R^○)S(O)₂NR^○ ₂；-N(R^○)S(O)₂R^○；-N(OR^○)R^○；-C(NH)NR^○ ₂；-P(O)_-4R^○；-P(O)R^○ ₂；-OP(O)R^○ ₂；-OP(O)(OR^○)₂；SiR^○ ₃；-(C_1-4Straight or branched alkylidene) O N (R^○)₂；Or-(C_1-4Straight or branched alkylidene) C (O) O-N (R^○)₂, The most each R^○Can be replaced as defined belowly and independently be hydrogen, C_1-6Aliphatic series ,-CH₂Ph、-O(CH₂)₀-₁Ph, or tool Have that 0-4 is saturated independently selected from the heteroatomic 5-6 unit of nitrogen, oxygen or sulfur, part is unsaturated or aryl rings, or despite with Upper definition, but two independent R occurred^○Formed together with the atom between them have 0-4 independently selected from nitrogen, oxygen or The heteroatomic 3-12 unit of sulfur is saturated, part is unsaturated or aryl monocycle or multi-ring, and it can be replaced as defined belowly.

R^○(or two independent R occurred^○The ring formed together with the atom between them) on suitable unit price replace Base independently be halogen ,-(CH₂)_0-2R^●,-(halo R^●)、-(CH₂)_0-2OH、-(CH₂)_0-2OR^●、-(CH₂)_0-2CH(OR^●)₂；-O (halo R^●)、-CN、-N₃、-(CH₂)_0-2C(O)R^●、-(CH₂)_0-2C(O)OH、-(CH₂)_0-2C(O)OR^●、-(CH₂)_0-2SR^●、- (CH₂)_0-2SH、-(CH₂)_0-2NH₂、-(CH₂)_0-2NHR^●、-(CH₂)_0-2NR^● ₂、-NO₂、-SiR^● ₃、-OSiR^● ₃、-C(O)SR^●、- (C_1-4Straight or branched alkylidene) C (O) OR^●Or-SSR^●, the most each R^●Unsubstituted or when above there being " halogeno-group " only By one or more halogen substiuted, and independently selected from C_1-4Aliphatic series ,-CH₂Ph、-O(CH₂)_0-1Ph, or there is 0-4 independently Ground is saturated selected from the heteroatomic 5-6 unit of nitrogen, oxygen or sulfur, part is unsaturated or aryl rings.R^○Saturated carbon atom on suitable Divalent substituent include=O and=S.

Suitable divalent substituent on the saturated carbon atom of " optionally substituted " group includes following :=O ,=S ,= NNR^* ₂,=NNHC (O) R^*,=NNHC (O) OR^*,=NNHS (O)₂R^*,=NR^*,=NOR^*、-O(C(R^* ₂))₂-₃O-or-S (C (R^* ₂))₂-₃S-, the most each independent R occurred^*Selected from hydrogen, can be as defined below the C that is replaced₁-₆Aliphatic or unsubstituted Have that 0-4 is saturated independently selected from the heteroatomic 5-6 unit of nitrogen, oxygen or sulfur, part is unsaturated or aryl rings.With " optional Ground is substituted " the suitable divalent substituent of the neighbouring substitutable carbon of group combination includes :-O (CR^* ₂)₂-₃O-, the most each solely The vertical R occurred^*Selected from hydrogen, can be as defined below the C that is replaced_1-6Aliphatic or unsubstituted have 0-4 independently selected from The heteroatomic 5-6 unit of nitrogen, oxygen or sulfur is saturated, part is unsaturated or aryl rings.

At R^*Aliphatic group on suitable substituent group include halogen ,-R^●,-(halo R^●)、-OH、-OR^●,-O (halo R^●)、-CN、-C(O)OH、-C(O)OR^●、-NH₂、-NHR^●、-NR^● ₂Or-NO₂, the most each R^●Unsubstituted or ought above have " halogen Dai Ji " time only by one or more halogen substiuted, and independently be C_1-4Aliphatic series ,-CH₂Ph、-O(CH₂)₀-₁Ph or there is 0-4 The individual heteroatomic 5-6 unit independently selected from nitrogen, oxygen or sulfur is saturated, part is unsaturated or aryl rings.

The suitable substituent group that may replace on nitrogen of " optionally substituted " group includes The most eachIndependently be hydrogen, can determine as following The C that free burial ground for the destitute is replaced_1-6-OPh or unsubstituted aliphatic, unsubstituted has 0-4 independently selected from nitrogen, oxygen or sulfur Heteroatomic 5-6 unit is saturated, part is unsaturated or aryl rings, or despite defined above, two independent appearanceWith it Atom between is formed together unsubstituted to be had 0-4 and satisfies independently selected from the heteroatomic 3-12 unit of nitrogen, oxygen or sulfur Or aryl monocycle unsaturated with, part or dicyclo.

Aliphatic group on suitable substituent group independently be halogen ,-R^●,-(halo R^●)、-OH、-OR^●、-O (halo R^●)、-CN、-C(O)OH、-C(O)OR^●、-NH₂、-NHR^●、-NR^● ₂Or-NO₂, the most each R^●Unsubstituted or current Only by one or more halogen substiuted when face has " halogeno-group ", and independently be C_1-4Aliphatic series ,-CH₂Ph、-O(CH₂)_0-1Ph or The heteroatomic 5-6 unit independently selected from nitrogen, oxygen or sulfur is saturated, part is unsaturated or aryl rings to have 0-4.

As used herein, term " inhibitor " is defined as the mesh combining and/or suppressing to have measurable affinity The compound of mark 2-oxoglutaric acid dependent form enzyme.In certain embodiments, inhibitor have less than about 50 μMs, less than about 1 μM, Less than about 500nM, less than about 100nM or the IC of less than about 10nM₅₀And/or binding constant.

As used herein, term " measurable affinity " and " measurably suppression " mean to comprise the compound of offer Or the sample of a combination thereof and at least one 2-oxoglutaric acid dependent form enzyme comprises with in the absence of described compound or a combination thereof Between the equivalent sample of at least one 2-oxoglutaric acid dependent form enzyme, at least one 2-oxoglutaric acid dependent form enzymatic activity surveys Amount changes.

" pharmaceutically acceptable salt " includes acid-addition salts and base addition salts." pharmaceutically acceptable acid-addition salts " Refer to keep the biological effectiveness of free alkali and characteristic and be not at biology or other aspects those salt undesirable, this A little salt are and mineral acid that example hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, carbonic acid, phosphoric acid etc. are formed；And organic acid is selected from fat The organic acid of race, cyclic aliphatic, aromatics, araliphatic, heterocycle, carboxylic acid and sulphonic acids, such as formic acid, acetic acid, propanoic acid, glycolic, Portugal Saccharic acid, lactic acid, acetone acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, Radix Asparagi ammonia Acid, ascorbic acid, glutamic acid, ortho-aminobenzoic acid, benzoic acid, cinnamic acid, mandelic acid, palmoxiric acid (embonicacid), benzene second Acid, methanesulfonic acid, ethyl sulfonic acid, benzenesulfonic acid, p-methyl benzenesulfonic acid, salicylic acid etc..

" pharmaceutically acceptable base addition salts " includes those salt derived from inorganic base, such as sodium salt, potassium salt, lithium salts, ammonium Salt, calcium salt, magnesium salt, iron salt, zinc salt, mantoquita, manganese salt, aluminium salt etc..Concrete base addition salts be ammonium salt, potassium salt, sodium salt, calcium salt and Magnesium salt.Salt derived from pharmaceutically acceptable organic nontoxic alkali includes that primary amine, secondary amine and tertiary amine, substituted amine (include natural Replacement amine, cyclammonium and the deacidite existed, such as 2-aminopropane., trimethylamine, diethylamine, triethylamine, tripropyl amine (TPA), second Hydramine, 2-diethylaminoethanol, trometamol, hexanamine, lysine, arginine, histidine, caffeine, procaine, Kazakhstan Amine, choline, glycine betaine, ethylenediamine, glycosamine, methylglucosamine, theobromine, purine, piperazine, piperidines, N-ethylpiperidine, polyamines Resin etc.) salt.Concrete organic nontoxic alkali be 2-aminopropane., diethylamine, ethanolamine, trometamol, hexanamine, choline and Caffeine.

Term " tautomer " or " tautomeric form " refer to come the difference of mutual inversion of phases via low-yield potential barrier The constitutional isomer of energy.Such as, proton tautomer (also referred to as prototropic tautomeric body) includes moving via proton The mutual inversion of phases moved, such as keto-enol isomerization and imine-enamine isomerizations.Atomicity tautomer includes by some keys The restructuring closing electronics carrys out mutual inversion of phases.

" solvate " refers to one or more solvent molecule and the association of the compound of the present invention or compound.The reality of solvent Example includes water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid and ethanolamine.Term " hydrate " refers to the most molten Agent molecule is the complex of water.

" therapeutically effective amount " refers to the amount of the compounds of this invention, and its (i) treats specific disease, condition of illness or disease；(ii) Weaken, improve or eliminate one or more symptoms of specific disease, situation or disease；Or (iii) prevent or delay herein The outbreak of one or more symptoms of described specific disease, situation or disease.In the case of cancer, the treatment of medicine has Effect amount can reduce the quantity of cancerous cell；Reduce the size of tumor；Suppression (slow down i.e., to a certain extent and preferably stop) cancer is thin Born of the same parents' infiltration to peripheral organs；Suppression (slow down i.e., to a certain extent and preferably stoping) neoplasm metastasis；To a certain extent Suppression tumor growth；And/or alleviate one or more symptoms relevant to cancer to a certain extent.For the treatment of cancer, Effect can such as be measured by assessment disease developing time (TTP) and/or mensuration response rate (RR).Situation at immune disorder Under, therapeutically effective amount is symptom or the acute inflammation that be enough to reduce or alleviate allergic conditions, autoimmune disease and/or inflammatory diseases The amount of the symptom of disease reaction (such as, asthma).In some embodiments, therapeutically effective amount is chemical entities as herein described foot To substantially reduce activity or the amount of quantity of the cancerous cell of drug resistance or lasting drug resistance.

" treatment (treatment) " (and variant such as " treatment (treat) " or " treatment (treating) ") refers to that attempt changes Become or the clinical intervention of cell nature process individual by treatment, and can implement or during clinical pathology to prevent Implement.Treatment wishes that the effect reached includes one or more of: stop generation or recurrence, relief of symptoms, the elimination of disease Any direct or indirect pathology results of disease, the state of stable (i.e., no longer deteriorating) disease, prevent transfer, reduce disease The speed of process, state of improving or palliate a disease, extend survival period and disappearing compared with expection survival period when not accepting treatment Move back or improve prognosis.In certain embodiments, compound of formula I for delay disease or the development of disease or slow down disease or The process of disease.Those individualities needing treatment include those individualities having suffered from condition of illness or disease and are prone to suffer from condition of illness Or those condition of illness individual or to be prevented of disease (such as, by gene mutation or gene or protein unconventionality expression) Or those individualities of disease.

The explanation of exemplary compounds

In certain embodiments, the present invention provides compound of formula I:

Or its pharmaceutically acceptable salt, wherein R¹With ring A be as defined herein with describe.

As described in the most substantially, R¹For-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C (O)N(R′)₂、-C(O)SR、-C(O)C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、- SO₂N(R′)₂、-N(R′)C(O)R、-N(R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N (R′)₂,-N (R ') C (=N (R ')) N (R ')₂,-C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or- OC(O)N(R′)₂, wherein R and R ' is as hereinbefore defined with described herein.In some embodiments, R¹For hydrogen.One In a little embodiments, R¹For optionally substituted C_1-6Aliphatic series.In certain embodiments, R¹For optionally substituted C_1-6Alkyl, C_1-6Thiazolinyl or C_1-6Alkynyl.In certain embodiments, R¹For optionally substituted C_1-6Alkyl.In certain embodiments, R¹ For methyl.At some in other embodiment, R¹For ethyl or the tert-butyl group.In some embodiments, R¹For-OR ,-SR or- N(R′)₂.In certain embodiments, R¹For SR.In certain embodiments, R¹For NH₂.In certain embodiments, R¹ For-CN or-NO₂.In some embodiments, R¹For halogen.In certain embodiments, R¹For fluorine, chlorine, bromine or iodine.At some In embodiment, R¹For fluorine.In some embodiments, R¹For-C (O) R ,-CO₂R、-C(O)SR、-C(O)N(R′)₂、-C(O)C (O) R or-C (O) CH₂C(O)R.In certain embodiments, R¹For C (S) OR or C (S) N (R ')₂.In other embodiments In, R¹For-S (O) R ,-SO₂R or-SO₂N(R′)₂.In some embodiments, R¹For-N (R ') C (O) R ,-N (R ') C (O) N (R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂Or-N (R ') C (=N (R ')) N (R ')₂.Real at some Execute in scheme, R¹For-N (R ') N (R ')₂.In some embodiments, R¹For-C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N(R′)₂,-OC (O) R or-OC (O) N (R ')₂.As described in the most substantially, ring A is Wherein X, R²、R^2′、R³、R⁵ And R⁶For as hereinbefore defined with described herein.Therefore, in certain embodiments, the compound of the present invention has following One of structural formula:

Wherein R¹、R²、R^2′、R³、R⁵、R⁶It is as hereinbefore defined with described herein with X.

As described in the most substantially, R²For-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O) N(R′)₂、-C(O)SR、-C(O)C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N (R′)₂、-N(R′)C(O)R、-N(R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂、-N (R ') C (=N (R ')) N (R ')₂,-C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R′)₂, wherein R and R ' is as hereinbefore defined with described herein.In some embodiments, R²For hydrogen.Implement at some In scheme, R²For optionally substituted C_1-6Aliphatic series.In certain embodiments, R²For optionally substituted C_1-6Alkyl, C_1-6Alkene Base or C_1-6Alkynyl.In certain embodiments, R²For optionally substituted C_1-6Alkyl.In certain embodiments, R²For second Base.In certain other embodiments, R²For methyl, propyl group, isopropyl, butyl or isobutyl group.In some embodiments, R² For by-OH or-OC_1-6The substituted C of alkyl_1-6Alkyl.In certain embodiments, R²For-CH₂CH₂OH or-CH₂CH₂OCH₃.? In some embodiments, R²For cycloalkyl.In certain embodiments, R²For cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl.? In some embodiments, R²For optionally substituted C_1-6Thiazolinyl.In certain embodiments, R²For pi-allyl.Implement at some In scheme, R²For optionally substituted C_1-6Alkynyl.In certain embodiments, R²For 2-propynyl.In some embodiments, R²For optionally substituted benzyl.In certain embodiments, R²For unsubstituted benzyl.In certain other embodiments, R² For substituted benzyl.In some embodiments, R²For the C replaced by ester group_1-6Alkyl.In certain embodiments, R²For- CH₂CO₂C_1-6Alkyl or-CH₂CO₂Aryl.In certain embodiments, R²For-CH₂CO₂CH₂CH₃.In some embodiments, R²For-OR ,-SR or-N (R ')₂.In certain embodiments, R²For-CN or-NO₂.In some embodiments, R²For halogen. In certain embodiments, R²For fluorine, chlorine, bromine or iodine.In some embodiments, R²For-C (O) R ,-CO₂R、-C(O)SR、-C (O)N(R′)₂,-C (O) C (O) R or-C (O) CH₂C(O)R.In certain embodiments, R²For-C (S) OR or-C (S) N (R ')₂。 In other embodiments, R²For-S (O) R ,-SO₂R or-SO₂N(R′)₂.In some embodiments, R²For-N (R ') C (O) R、-N(R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂Or-N (R ') C (=N (R ')) N (R′)₂.In some embodiments, R²For-C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O)N(R′)₂。

As described in the most substantially, R²For-R ,-OR ,-SR ,-N (R ')₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O) SR、-C(O)C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C (O)R、-N(R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R′)₂,-C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂, wherein R and R ' is As hereinbefore defined with described herein.In some embodiments, R^2′For hydrogen.In some embodiments, R^2′For optionally The substituted C in ground_1-6Aliphatic series.In certain embodiments, R^2′For optionally substituted C_1-6Alkyl, C_1-6Thiazolinyl or C_1-6Alkynyl.? In some embodiment, R^2′For optionally substituted C_1-6Alkyl.In certain embodiments, R^2′For ethyl.At some other In embodiment, R^2′For methyl, propyl group, isopropyl, butyl or isobutyl group.In some embodiments, R^2′For by-OH or- OC_1-6The substituted C of alkyl_1-6Alkyl.In certain embodiments, R^2′For-CH₂CH₂OH or-CH₂CH₂OCH₃.Some embodiment party In case, R^2′For cycloalkyl.In certain embodiments, R^2′For cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl.Implement at some In scheme, R^2′For optionally substituted C_1-6Thiazolinyl.In certain embodiments, R^2′For pi-allyl.In some embodiments, R^2′For optionally substituted C_1-6Alkynyl.In certain embodiments, R^2′For 2-propynyl.In some embodiments, R^2′For Optionally substituted benzyl.In certain embodiments, R^2′For unsubstituted benzyl.At some in other embodiment, R^2′ For substituted benzyl.In some embodiments, R^2′For the C replaced by ester group_1-6Alkyl.In certain embodiments, R^2′For- CH₂CO₂C_1-6Alkyl or-CH₂CO₂Aryl.In certain embodiments, R^2′For-CH₂CO₂CH₂CH₃.In some embodiments, R^2′For-OR ,-SR or-N (R ')₂.In some embodiments, R^2′For-C (O) R ,-CO₂R、-C(O)SR、-C(O)N(R′)₂、-C (O) C (O) R or-C (O) CH₂C(O)R.In certain embodiments, R^2′For-C (S) OR or-C (S) N (R ')₂.Implement at other In scheme, R^2′For-S (O) R ,-SO₂R or-SO₂N(R′)₂.In some embodiments, R^2′For-N (R ') C (O) R ,-N (R ') C (O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂Or-N (R ') C (=N (R ')) N (R ')₂.One In a little embodiments, R^2′For-C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂。

As described in the most substantially, R³For-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O) N(R′)₂、-C(O)C(O)R、-C(O)CH₂C(O)R、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N(R′)C(O)N (R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-C=NN (R ')₂,-C=NOR ,-OC (O) R or-OC (O)N(R′)₂, wherein R and R ' is as hereinbefore defined with described herein.In some embodiments, R³For hydrogen.At some In embodiment, R³For optionally substituted C_1-6Aliphatic series.In certain embodiments, R³For optionally substituted C_1-6Alkyl, C_1-6Thiazolinyl or C_1-6Alkynyl.In certain embodiments, R³For optionally substituted C_1-6Alkyl.In certain embodiments, R³ For methyl.In certain other embodiments, R³For ethyl, propyl group, isopropyl, butyl or isobutyl group.In some embodiment In, R³For-CF₃.In some embodiments, R³For the C replaced by OH_1-6Alkyl or OC_1-6Alkyl.In some embodiment In, R³For-CH₂OH、-CH₂CH₂OH、-CH₂CH₂CH₂OH、-CH₂OCH₂CH₃、-CH₂OCH₃、-CH₂CH₂CH₂OCH₃、-CH(OH)CH₃ Or-CH₂CH₂OCH₃.In some embodiments, R³For by-NHC_1-6Alkyl or-N (C_1-6Alkyl)₂The substituted C of group_1-6Alkyl. In certain embodiments, R³For-CH₂NHC_1-6Alkyl.In certain embodiments, R³For-CH₂NHCH₃.Some embodiment party In case, R³For the C replaced by aryl, heteroaryl, carbocylic radical or heterocyclic ring_1-6Alkyl.In some embodiments, R³For optionally The substituted benzyl in ground.In certain embodiments, R³For unsubstituted benzyl.In certain other embodiments, R³For substituted Benzyl.In certain embodiments, R³For-C (R^○)₂Ph.In certain embodiments, R³For-C (R^○)₂Ph, wherein R^○For hydrogen Or methyl.In certain embodiments, R³For trifluoromethyl benzyl.In certain embodiments, R³For-C (R^○)₂(heteroaryl). In certain embodiments, R³For-C (R^○)₂(heteroaryl), wherein said heteroaryl is pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazine Base, triazine radical, pyriconyl, pyrrole radicals, pyrazolyl, imidazole radicals, triazolyl, tetrazole radical, thienyl, furyl, thiazolyl, different Thiazolyl, thiadiazolyl group, oxazolyl, isoxazolyl or di azoly.In certain embodiments, R³For-CH₂(heteroaryl), its Described in heteroaryl be pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, triazine radical, pyrrole radicals, pyrazolyl, imidazole radicals, triazolyl, Tetrazole radical, thienyl, furyl, thiazolyl, isothiazolyl, thiadiazolyl group, oxazolyl, isoxazolyl or di azoly.At certain In a little embodiments, R³For-C (R^○)₂(carbocylic radical).In certain embodiments, R³For-C (R^○)₂(carbocylic radical), wherein said Carbocylic radical is cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl or suberyl.In certain embodiments, R³For-CH₂(carbocylic radical), Wherein said carbocylic radical is cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl or suberyl.In certain embodiments, R³For-C (R^○)₂(heterocyclic radical).In certain embodiments, R³For-C (R^○)₂(heterocyclic radical), wherein said heterocyclic radical be tetrahydrofuran base, four Hydrogen thienyl, THP trtrahydropyranyl, pyrrolidinyl, pyrrolidone-base, piperidyl, pyrrolinyl, tetrahydric quinoline group, tetrahydroisoquinoline Base, decahydroquinolyl, oxazolidinyl, piperazinyl, dialkyl group, dioxolanyl, diazaBase, oxygen azepineBase, sulfur nitrogen MiscellaneousBase, morpholino and quininuclidinyl.In certain embodiments, R³For-CH₂(heterocyclic radical), wherein said heterocyclic radical is four Hydrogen furyl, tetrahydro-thienyl, THP trtrahydropyranyl, pyrrolidinyl, pyrrolidone-base, piperidyl, pyrrolinyl, tetrahydroquinoline Base, tetrahydro isoquinolyl, decahydroquinolyl, oxazolidinyl, piperazinyl, dialkyl group, dioxolanyl, diazaBase, oxygen AzepineBase, sulfur azepineBase, morpholino and quininuclidinyl.In some embodiments, R³For optionally substituted C_1-6Alkene Base.In certain embodiments, R³For pi-allyl.In some embodiments, R³For optionally substituted C_1-6Alkynyl.At some In embodiment, R³For propargyl.In some embodiments, R³For optionally substituted aryl or heteroaryl.Implement at some In scheme, R³For phenyl.In certain embodiments, R³For substituted phenyl.In certain embodiments, R³For toluyl Base.In certain other embodiments, R³For there is 1-3 selected from nitrogen, oxygen and the heteroatomic 5-6 unit hetero-aromatic ring of sulfur.At certain In a little embodiments, R³For pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, triazine radical, pyrrole radicals, pyrazolyl, imidazole radicals, triazole Base, tetrazole radical, thienyl, furyl, thiazolyl, isothiazolyl, thiadiazolyl group, oxazolyl, isoxazolyl or di azoly.? In some embodiments, R³For-OR ,-SR or-N (R ')₂.In some embodiments, R³For halogen.In some embodiment In, R³For fluorine, chlorine, bromine or iodine.In some embodiments, R³For-C (O) R ,-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C (O) C (O) R or-C (O) CH₂C(O)R.In certain embodiments, R³For optionally substituted-CO₂C_1-6Alkyl.Real at some Execute in scheme, R³For-CO₂Et or-CO₂Bn.In certain embodiments, R³For-CONHC_1-6Alkyl.In some embodiment In, R³For-CONHCH₃Or-CONHCH₂CH₃.In certain embodiments, R³For C (S) OR or C (S) N (R ')₂.Real at other Execute in scheme, R³For-S (O) R ,-SO₂R or-SO₂N(R′)₂.In some embodiments, R³For-N (R ') C (O) R ,-N (R ') C (O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂Or-N (R ') C (=N (R ')) N (R ')₂.One In a little embodiments, R³For-C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂。

In some embodiments, R²And R³Formed together with the atom between them and optionally substituted there is 0-4 solely On the spot selected from the unsaturated ring of heteroatomic 5-7 unit part or the aromatic condensed ring of nitrogen, oxygen and sulfur.In certain embodiments, R²And R³ 5 yuan of condensed ring are formed together with the atom between them.In certain embodiments, R²And R³Shape together with the atom between them Become the cyclopentenes ring condensed.In certain embodiments, R²And R³6 yuan of condensed ring are formed together with the atom between them.At some In embodiment, R²And R³The cyclohexene ring condensed is formed together with the atom between them.In certain embodiments, R²With R³Fused benzene rings is formed together with the atom between them.In certain embodiments, R²And R³Together with the atom between them Formed and there is 1-4 the unsaturated condensed ring of heteroatomic 5-7 unit part independently selected from nitrogen, oxygen and sulfur.In some embodiment In, R²And R³Formed together with the atom between them and there is 1-4 the heteroatomic 5-7 unit virtue independently selected from nitrogen, oxygen and sulfur Fragrant condensed ring.

In some embodiments, R^2′And R³Formed together with the atom between them and optionally substituted there is 1-4 The unsaturated ring of heteroatomic 5-7 unit part or aromatic condensed ring independently selected from nitrogen, oxygen and sulfur.In certain embodiments, R^2′ And R³5 yuan of condensed ring are formed together with the atom between them.In certain embodiments, R^2′And R³And the atom one between them Rise and form 6 yuan of condensed ring.In certain embodiments, R^2′And R³The pyridine ring condensed is formed together with the atom between them.? In some embodiment, R^2′And R³Formed together with the atom between them and there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 1-4 The unsaturated condensed ring of 5-7 unit part of atom.In certain embodiments, R^2′And R³Formed together with the atom between them and have 1-4 the heteroatomic 5-7 unit aromatic condensed ring independently selected from nitrogen, oxygen and sulfur.

As described in the most substantially, X is-N (R⁴)-,-O-or-S-, wherein R⁴For as hereinbefore defined with described herein. In certain embodiments, X is-O-or-S-.In some embodiments, X is-N (R⁴)-.In certain embodiments, X For-NH-.In certain embodiments, X is-N (CH₃)-。

As described in the most substantially, R⁴For-R ,-C (O) R ,-CO₂R or-S (O)₂R, or R⁴And R³And the atom between them Formed together and optionally substituted have that 1-4 is saturated independently selected from the heteroatomic 5-7 unit of nitrogen, oxygen and sulfur, part insatiable hunger With or aromatic condensed ring.In certain embodiments, R⁴For hydrogen.In some embodiments, R⁴For optionally substituted C_1-6Alkyl. In certain embodiments, R⁴For optionally substituted C_1-3Alkyl.In certain embodiments, R⁴For methyl.Implement at some In scheme, R⁴For substituted C_1-6Alkyl.In certain embodiments, R⁴For benzyl.In certain embodiments, R⁴For- CH₂CH₂N(CH₃)₂.In some embodiments, R⁴For aryl or heteroaryl.In certain embodiments, R⁴For phenyl.One In a little embodiments, R⁴For-C (O) R ,-CO₂R or-S (O)₂R。

In some embodiments, R⁴And R³Formed together with the atom between them and optionally substituted there is 1-4 solely On the spot the heteroatomic 5-7 unit selected from nitrogen, oxygen and sulfur is saturated, part is unsaturated or aromatic condensed ring.In certain embodiments, R⁴ And R³5 yuan of condensed ring are formed together with the atom between them.In certain embodiments, R⁴And R³And the atom one between them Rise and form the pyrrolidine ring condensed.In certain embodiments, R⁴And R³6 yuan of condensed ring are formed together with the atom between them.? In some embodiment, R⁴And R³The piperidine ring condensed is formed together with the atom between them.In certain embodiments, R⁴ And R³Formed together with the atom between them and there is 1-4 the heteroatomic 5-7 unit part independently selected from nitrogen, oxygen and sulfur not Saturated condensed ring.In certain embodiments, R⁴And R³Formed together with the atom between them have 1-4 independently selected from nitrogen, The heteroatomic 5-7 unit aromatic condensed ring of oxygen and sulfur.

As described in the most substantially, R⁵For R ,-C (O) R ,-CO₂R、-C(O)N(R′)₂,-C (O) C (O) R or-C (O) CH₂C(O) R, or R⁵And R²Formed together with the atom between them and optionally substituted there is 1-4 independently selected from nitrogen, oxygen and sulfur The unsaturated ring of heteroatomic 5-7 unit part or aromatic condensed ring.In some embodiments, R⁵For hydrogen.In some embodiments, R⁵For optionally substituted C_1-6Alkyl.In certain embodiments, R⁵For methyl.In certain embodiments, R⁵For substituted C_1-6Alkyl.In certain embodiments, R⁵For by-OH or-OC_1-6The substituted C of alkyl_1-6Alkyl.In certain embodiments, R⁵ For-CH₂CH₂OCH₃.In some embodiments, R⁴For-C (O) R ,-CO₂R、-C(O)N(R′)₂,-C (O) C (O) R or-C (O) CH₂C(O)R。

As described in the most substantially, R⁶For-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O) N(R′)₂、-C(O)SR、-C(O)C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N (R′)₂、-N(R′)C(O)R、-N(R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂、-N (R ') C (=N (R ')) N (R ')₂,-C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R′)₂, wherein R and R ' is as hereinbefore defined with described herein.In some embodiments, R⁶For hydrogen.Implement at some In scheme, R⁶For optionally substituted C_1-6Aliphatic series.In certain embodiments, R⁶For optionally substituted C_1-6Alkyl, C_1-6Alkene Base or C_1-6Alkynyl.In certain embodiments, R⁶For optionally substituted C_1-6Alkyl.In certain embodiments, R⁶For second Base.In certain other embodiments, R⁶For methyl, propyl group, isopropyl, butyl or isobutyl group.In some embodiments, R⁶ For the C replaced by OH_1-6Alkyl or OC_1-6Alkyl.In certain embodiments, R⁶For-CH₂CH₂OH or-CH₂CH₂OCH₃.? In some embodiments, R⁶For cycloalkyl.In certain embodiments, R⁶For for cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl. In some embodiments, R⁶For optionally substituted C_1-6Thiazolinyl.In certain embodiments, R⁶For pi-allyl.Real at some Execute in scheme, R⁶For optionally substituted C_1-6Alkynyl.In certain embodiments, R⁶For 2-propynyl.In some embodiments In, R⁶For optionally substituted benzyl.In certain embodiments, R⁶For unsubstituted benzyl.In some other embodiment In, R⁶For substituted benzyl.In some embodiments, R⁶For the C replaced by ester group_1-6Alkyl.In certain embodiments, R⁶ For CH₂CO₂C_1-6Alkyl or CH₂CO₂Aryl.In certain embodiments, R⁶For-CH₂CO₂CH₂CH₃.In some embodiments In, R⁶For-OR ,-SR or-N (R ')₂.In certain embodiments, R⁶For CN or NO₂.In some embodiments, R⁶For halogen Element.In certain embodiments, R⁶For fluorine, chlorine, bromine or iodine.In some embodiments, R⁶For-C (O) R ,-CO₂R、-C(O) SR、-C(O)N(R′)₂,-C (O) C (O) R or-C (O) CH₂C(O)R.In certain embodiments, R⁶For C (S) OR or C (S) N (R′)₂.In other embodiments, R⁶For-S (O) R ,-SO₂R or-SO₂N(R′)₂.In some embodiments, R⁶For-N (R ') C(O)R、-N(R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂Or-N (R ') C (=N (R′))N(R′)₂.In some embodiments, R⁶For-C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂、-OC(O)R Or-OC (O) N (R ')₂。

In some embodiments, R⁶And R³Formed together with the atom between them and optionally substituted there is 0-4 solely On the spot selected from the unsaturated ring of heteroatomic 5-7 unit part or the aromatic condensed ring of nitrogen, oxygen and sulfur.In certain embodiments, R⁶And R³ 5 yuan of condensed ring are formed together with the atom between them.In certain embodiments, R⁶And R³Shape together with the atom between them Become the cyclopentenes ring condensed.In certain embodiments, R⁶And R³6 yuan of condensed ring are formed together with the atom between them.At some In embodiment, R⁶And R³The cyclohexene ring condensed is formed together with the atom between them.In certain embodiments, R⁶With R³Fused benzene rings is formed together with the atom between them.In certain embodiments, R⁶And R³Together with the atom between them Formed and there is 1-4 the unsaturated condensed ring of heteroatomic 5-7 unit part independently selected from nitrogen, oxygen and sulfur.In some embodiment In, R⁶And R³Formed together with the atom between them and there is 1-4 the heteroatomic 5-7 unit virtue independently selected from nitrogen, oxygen and sulfur Fragrant condensed ring.

As described in the most substantially, each R independently be hydrogen or the optionally substituted group selected from the following: C_1–6Fat Race, phenyl, the saturated or part unsaturated carbocyclic of 3-7 unit, 8-10 unit dicyclo is saturated, part is unsaturated or aromatic ring, has 1-3 solely On the spot selected from nitrogen, oxygen or the heteroatomic 5-6 unit monocycle hetero-aromatic ring of sulfur, there is 1-2 miscellaneous former independently selected from nitrogen, oxygen or sulfur Saturated or the part unsaturated heterocycle of 4-7 unit of son, to have 1-4 the heteroatomic 7-10 unit independently selected from nitrogen, oxygen or sulfur double Ring filling or part unsaturated heterocycle or there is 1-4 the heteroatomic 8-10 unit dicyclo heteroaryl independently selected from nitrogen, oxygen or sulfur Ring；In certain embodiments, R is hydrogen.In some embodiments, R is optionally substituted C_1-6Alkyl, alkenyl or alkynyl. In certain embodiments, R is optionally substituted C_1-6Alkyl.In certain embodiments, R is unsubstituted C_1-6Alkyl. In certain embodiments, R is substituted C_1-6Alkyl.In certain embodiments, R is methyl, ethyl, propyl group, butyl, different Propyl group, isobutyl group, pi-allyl or benzyl.

In some embodiments, R is the saturated or part unsaturated carbocyclic of 3-7 unit.In certain embodiments, R is 3-4 Unit's saturated carbon ring.In other embodiments, R is the saturated or part unsaturated carbocyclic of 5-7 unit.In certain embodiments, R is For cyclopropyl, cyclobutyl, cyclopenta, cyclopentenyl, cyclohexyl, cyclohexenyl group, suberyl or cycloheptenyl.

In some embodiments, R be have 1-2 saturated independently selected from the heteroatomic 4-7 unit of nitrogen, oxygen or sulfur or Part unsaturated heterocycle.In certain embodiments, R is 4-7 unit saturated heterocyclic.In other embodiments, R is 5-7 unit Part unsaturated heterocycle.In certain embodiments, R be tetrahydrofuran base, tetrahydro-thienyl, THP trtrahydropyranyl, pyrrolidinyl, Pyrrolidone-base, piperidyl, pyrrolinyl, oxazolidinyl, piperazinyl, dialkyl group, dioxolanyl, diazaBase, oxygen AzepineBase, sulfur azepineBase or morpholino.

In some embodiments, R is that 8-10 unit dicyclo is saturated or part unsaturated carbocyclic or have 1-4 and select independently Saturated or the part unsaturated heterocycle from the heteroatomic 7-10 unit dicyclo of nitrogen, oxygen or sulfur.In certain embodiments, R is decahydro Naphthyl, tetralyl or decahydronaphthalenes.In certain other embodiments, R is tetrahydric quinoline group, tetrahydro isoquinolyl or decahydro Quinolyl.In some embodiments, R is the heterocyclic ring being fused to aryl or heteroaryl ring.In certain embodiments, R For indolinyl, 3H-indyl, chromanyl, phenanthridinyl, 2-azabicyclic [2.2.1] heptane base, octahydro indole Base or tetrahydric quinoline group.

In some embodiments, R is phenyl or has 1-3 the heteroatomic 5-6 unit independently selected from nitrogen, oxygen or sulfur Heteroaryl ring.In certain embodiments, R is phenyl.In certain other embodiments, R is for having 1-3 selected from nitrogen, oxygen Or heteroatomic 5 yuan of heteroaryl rings of sulfur.In other embodiments, R is 6 yuan of heteroaryl rings with 1-3 nitrogen.At some In embodiment, R is phenyl, pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl or triazine radical.In certain other embodiments, R For pyrrole radicals, pyrazolyl, imidazole radicals, triazolyl, tetrazole radical, thienyl, furyl, thiazolyl, isothiazolyl, thiadiazolyl group, Oxazolyl, isoxazolyl or di azoly.

In some embodiments, R is Bicyclic aryl rings.In certain embodiments, R is naphthyl.In other embodiments In, R is to have 1-4 the heteroatomic 8-10 unit bicyclic heteroaryl ring independently selected from nitrogen, oxygen or sulfur.In some embodiment In, R is quinolyl, quinoxalinyl, quinazolyl, pyrido-pyrazine base or Pyridopyrimidine base.In some other embodiment In, R is indyl, benzimidazolyl, benzothiazolyl, benzofuranyl, benzotriazole base, benzoxazolyl group, benzothiophene Base, indazolyl, imidazopyridyl, imidazopyrimidine base, Imidazopyrazines base, Imidazopyridazine base, Pyrazolopyridine base, pyrrole Azoles pyrimidine radicals, pyrazolo pyrazinyl, pyrazolo pyridazine base, pyrrolo-thiazolyl, Imidazothiazole base, thiazolopyridinyl, Thiazolopyrimidinyl, thiazole pyrazinyl, thiazole pyridazinyl, azoles pyridine radicals, azoles pyrimidine radicals, azoles pyrazinyl Or azoles pyridazinyl.

As described in the most substantially, each R ' independently be R ,-C (O) R ,-CO₂R or two R ' on same nitrogen with Nitrogen between them is formed together has 1-2 the heteroatomic 4-7 unit heterocycle independently selected from nitrogen, oxygen and sulfur.Real at some Execute in scheme, R ' be as hereinbefore defined with describe R.In certain embodiments, R ' is-C (O) R or-CO₂R.At some In embodiment, formed together with two R ' on same nitrogen and the atom between them have 1-2 independently selected from nitrogen, oxygen and The heteroatomic 4-7 unit heterocycle of sulfur.In certain embodiments, shape together with two R ' on same nitrogen and the atom between them Become azetidine, pyrrolidine, piperidines, morpholine, piperazine, high piperidines or homopiperazine ring.

On the one hand according to, it is provided that compound there is Formula II:

Or its pharmaceutically acceptable salt, wherein R¹、R²、R³And R⁴For as defined herein with described.At some In embodiment, Formula II compound has with one of following formula:

On the other hand according to, it is provided that compound there is formula III:

Or its pharmaceutically acceptable salt, wherein R¹、R²、R³And R⁴For as defined herein with described.At some In embodiment, Formula II compound has with one of following formula:

On the other hand according to, it is provided that compound there is formula IV:

Or its pharmaceutically acceptable salt, wherein R¹、R²、R³And R⁵For as defined herein with described.At some In embodiment, R⁵For optionally substituted C_1-6Aliphatic series.In certain embodiments, R⁵For methyl.In some embodiments, R⁵For optionally substituted C_1-6Alkyl.In certain embodiments, R⁵For substituted C_1-6Alkyl.In certain embodiments, R⁵ For by-OH or-OC_1-6The substituted C of alkyl_1-6Alkyl.In certain embodiments, R⁵For-CH₂CH₂OMe。

On the other hand according to, it is provided that compound there is Formula V:

Or its pharmaceutically acceptable salt, wherein R¹、R^2′And R³For as defined herein with described.

Exemplary compound of formula I is listed in table 1 below.

The exemplary compound of formula I of table 1.:

In certain embodiments, the invention provides any compound that above table 1 described or it pharmaceutically can connect The salt being subject to.

In some embodiments, the invention provides the compound listed by table 1 below-a:

Table 1-a. compound of formula I:

In certain embodiments, the invention provides any compound that above table 1-a described or it pharmaceutically may be used The salt accepted.

In certain embodiments, present invention offer formula (I) compound, it is formula (II) compound:

Or its salt, wherein:

R¹For H, C_1-6Alkyl, trifluoromethyl, 3-6 unit carbocylic radical, 6 yuan of aryl, 3-6 unit heterocyclic radical, 5-6 unit heteroaryl, halogen Dai Ji ,-OR^f、-SR^f、-N(R^f)₂,-CN or-NO₂, wherein said alkyl, carbocylic radical, aryl, heteroaryl and heterocyclic radical are by one Or it is multiple independently selected from oxo base, halogeno-group, C_1-3Alkoxyl and C_1-3The group of alkyl optionally replaces；

R²And R³It is each independently H, C_1–12Alkyl, C_2–12Thiazolinyl, C_2–12Alkynyl, carbocylic radical, aryl, heterocyclic radical, heteroaryl Base, halogeno-group ,-OR^a、-SR^a、-N(R^a)₂、-CN、-NO₂、-C(O)R^a、-CO₂R^a、-C(O)N(R^a)₂、-C(O)SR^a、-C(O)C (O)R^a、-C(O)CH₂C(O)R^a、-C(S)N(R^a)₂、-C(S)OR^a、-S(O)R^a、-SO₂R^a、-SO₂N(R^a)₂,、-N(R^a)C(O) R^a、-N(R^a)C(O)N(R^a)₂,、-N(R^a)SO₂R^a、-N(R^a)SO₂N(R^a)₂、-N(R^a)N(R^a)₂、-N(R^a) C (=N (R^a))N (R^a)₂,-C (=N) N (R^a)₂,-C=NOR^a,-C (=N (R^a))N(R^a)₂、-OC(O)R^aOr-OC (O) N (R^a)₂, wherein R²And R³ C_1–12Alkyl, C_2–12Thiazolinyl, C_2–12Alkynyl, carbocylic radical, aryl, heteroaryl and heterocyclic radical are the most one or more R^xGroup optionally replaces；And wherein R²And R³It is not each H；Or R²And R³Form 4 together with the atom being connected with them, 5,6,7 or 8 yuan of carbocylic radicals or aryl, described carbocylic radical or aryl are by one or more R^xGroup optionally replaces；

R⁴For H, C_1-12Alkyl, C_2-12Thiazolinyl, C_2-12Alkynyl, carbocylic radical, aryl, heteroaryl and heterocyclic radical, wherein C_1-12 Alkyl, C_2-12Thiazolinyl, C_2-12Alkynyl, carbocylic radical, aryl, heteroaryl and heterocyclic radical each by one or more independently selected from oxygen Dai Ji, C_1-12Alkyl, C_1-12Haloalkyl, carbocylic radical, aryl, heterocyclic radical, heteroaryl, halogeno-group ,-CN ,-NO₂、-NR^mR^m、- OR^m,-C (=O) OR^mWith-OC (=O) R^mGroup optionally replace；Or R⁴And R³Formed miscellaneous together with the atom being connected with them Ring group；

Each R^aIndependently selected from H, C_1-6Alkyl, C_2-6Thiazolinyl, C_2-6Alkynyl, carbocylic radical, aryl, heteroaryl and heterocycle Base, wherein C_1-6Alkyl, C_3-6Thiazolinyl, C_3-6Alkynyl, carbocylic radical, aryl, heteroaryl and heterocyclic radical are each by one or more R^xBase Group optionally replaces；

Each R^fIndependently selected from H, C_1-3Alkyl, trifluoromethyl, 3-6 unit carbocylic radical, 6 yuan of aryl, 3-6 unit heterocyclic radical and 5-6 unit heteroaryl, or two R^f3-6 unit heterocycle is formed with them together with the nitrogen that group is connected；

Each R^gIndependently selected from H, C_1–6Alkyl, C_2–6Thiazolinyl, C_2–6Alkynyl, C_3-8Carbocylic radical, aryl, heteroaryl and miscellaneous Ring group, wherein C_1–6Alkyl, C_3–6Thiazolinyl, C_3-6Alkynyl, C_3-8Carbocylic radical, aryl, heteroaryl and heterocyclic radical are each by one or many Individual R^xGroup optionally replaces；Or two R^g3-6 unit heterocycle or 5-6 unit heteroaryl is formed with them together with the nitrogen that group is connected；

Each R^mIndependently selected from H, C_1-6Alkyl, C_2-6Thiazolinyl, C_2-6Alkynyl, C_1-6Haloalkyl, carbocylic radical, C_1-6Alkane acyl Base, phenyl and benzyl, any of which C_1-6Alkyl, C_2-6Thiazolinyl, C_2-6Alkynyl, C_1-6Haloalkyl, carbocylic radical, C_1-6Alkanoyl, Phenyl and benzyl by one or more independently selected from halogeno-group ,-CN ,-NO₂、-NR^yR^zAnd OR^wGroup optionally replace； Or two R^m3-6 unit heterocycle is formed with them together with the nitrogen that group is connected；

Each R^vIndependently be hydrogen, C_1-6Alkyl, C_2-6Thiazolinyl, C_2-6Alkynyl, carbocylic radical, aryl, heteroaryl and heterocyclic radical, Wherein C_1-6Alkyl, C_2-6Thiazolinyl, C_2-6Alkynyl, carbocylic radical, aryl, heteroaryl and heterocyclic radical each by one or more independently Selected from oxo base, halogeno-group, amino, hydroxyl, aryl, carbocylic radical and C₁-C₆Alkyl (its by one or more independently selected from The group of oxo base and halogeno-group optionally replaces) group optionally replace；Or two R^vTogether with the nitrogen being connected with them Formed by one or more independently selected from oxo base, halogeno-group and C_1-3Alkyl (its by one or more independently selected from oxo The group of base and halogeno-group optionally replaces) the optionally substituted heterocyclic radical of group；

Each R^wIndependently selected from H, C_1-4Alkyl, C_1-4Alkanoyl, phenyl, benzyl and phenethyl.

Each R^xIndependently selected from oxo base, C_1-6Alkyl, C_2-6Thiazolinyl, C_2-6Alkynyl, carbocylic radical, aryl, heteroaryl, miscellaneous Ring ,-F ,-Cl ,-Br ,-I ,-NO₂、-N(R^v)₂、-CN、-C(O)-N(R^v)₂、-S(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-O-R^v、- S-R^v、-O-C(O)-R^v、-O-C(O)-O-R^v、-C(O)-R^v、-C(O)-O-R^v、-S(O)-R^v、-S(O)₂-R^v、-O-C(O)-N (R^v)₂,、-N(R^v)-C(O)-OR^v、-N(R^v)-C(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-N(R^v)-C(O)-R^v、-N(R^v)-S (O)-R^v、-N(R^v)-S(O)₂-R^v、-N(R^v)-S(O)-N(R^v)₂And-N (R^v)-S(O)₂-N(R^v)₂, any of which C_1-6Alkane Base, C_2-6Thiazolinyl, C_2-6Alkynyl, carbocylic radical, aryl, heteroaryl and heterocycle by one or more independently selected from R^xa, oxo base, Halogeno-group ,-NO₂、-N(R^v)₂、-CN、-C(O)-N(R^v)₂、-S(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-O-R^v、-S-R^v、-O-C (O)-R^v、-C(O)-R^v、-C(O)-O-R^v、-S(O)-R^v、-S(O)₂-R^v、-C(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-N(R^v)-C (O)-R^v、-N(R^v)-C(O)-OR^v、-N(R^v)-S(O)-R^v、-N(R^v)-S(O)₂-R^vAnd C_1-6(they are one or more for alkyl Group independently selected from oxo base and halogeno-group optionally replaces) group optionally replace；

Each R^yAnd R^zIndependently selected from H, C_1-4Alkyl, C_1-4Alkanoyl, C_1-4Alkoxy carbonyl group, phenyl, benzyl and phenethyl, Or R^yAnd R^zHeterocyclic radical is formed together with the nitrogen being connected with them；

Each R^xaIndependently selected from aryl, heteroaryl, heterocycle and carbocylic radical, any of which aryl, heteroaryl, heterocyclic radical With carbocylic radical by one or more independently selected from C_1-6Alkyl, C_2-6Thiazolinyl, C_2-6Alkynyl ,-F ,-Cl ,-Br ,-I ,-NO₂、-N (R^v)₂,-CN, carbocyclic ring, aryl ,-C (O)-N (R^v)₂、-S(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-O-R^v、-S-R^v、-O-C(O)- R^v、-O-C(O)-O-R^v、-C(O)-R^v、-C(O)-O-R^v、-S(O)-R^v、-S(O)₂-R^v、-O-C(O)-N(R^v)₂、-N(R^v)-C (O)-OR^v、-N(R^v)-C(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-N(R^v)-C(O)-R^v、-N(R^v)、-S(O)-R^v、-N(R^v)-S (O)₂-R^vAnd-N (R^v)-S(O)-N(R^v)₂Group optionally replace, any of which C_1-6Alkyl, C_2-6Thiazolinyl and C_2-6Alkynes Base by one or more independently selected from oxo base, halogeno-group ,-NO₂、-N(R^v)₂、-CN、-C(O)-N(R^v)₂、-S(O)-N (R^v)₂、-S(O)₂-N(R^v)₂、-O-R^v、-S-R^v、-O-C(O)-R^v、-C(O)-R^v、-C(O)-O-R^v、-S(O)-R^v、-S(O)₂- R^v、-C(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-N(R^v)-C(O)-R^v、-N(R^v)-S(O)-R^vAnd-N (R^v)-S(O)₂-R^v's Group optionally replaces.

In certain embodiments, R¹For H, C_1-6Alkyl, trifluoromethyl, 3-6 unit carbocylic radical, 6 yuan of aryl, 3-6 unit heterocycles Base, 5-6 unit heteroaryl, halogeno-group ,-OR^f、-SR^f、-N(R^f)₂,-CN or-NO₂, wherein said alkyl, carbocylic radical, aryl, heteroaryl Base and heterocyclic radical by one or more independently selected from oxo base, halogeno-group, C_1-3Alkoxyl and C_1-3The group of alkyl is optional Ground replaces.

In certain embodiments, R¹For H, methyl or ethyl.

In certain embodiments, R¹For H.

In certain embodiments, R²For H.

In certain embodiments, R²For C_1-12Alkyl, C_2-12Thiazolinyl, C_2-12Alkynyl, carbocylic radical, aryl, heterocyclic radical, miscellaneous Aryl, halogeno-group ,-OR^a、-SR^a、-N(R^a)₂、-CN、-NO₂、-C(O)R^a、-CO₂R^a、-C(O)N(R^a)₂、-C(O)SR^a、-C(O)C (O)R^a、-C(O)CH₂C(O)R^a、-C(S)N(R^a)₂、-C(S)OR^a、-S(O)R^a、-SO₂R^a、-SO₂N(R^a)₂、-N(R^a)C(O)R^a、- N(R^a)C(O)N(R^a)₂、-N(R^a)SO₂R^a、-N(R^a)SO₂N(R^a)₂、-N(R^a)N(R^a)₂、-N(R^a) C (=N (R^a))N(R^a)₂、-C (=N) N (R^a)₂,-C=NOR^a,-C (=N (R^a))N(R^a)₂、-OC(O)R^aOr-OC (O) N (R^a)₂, wherein R²C_1-12Alkyl, C_2-12Thiazolinyl, C_2-12Alkynyl, carbocylic radical, aryl, heteroaryl and heterocyclic radical are each by one or more R^xGroup is individually optionally Replace.

In certain embodiments, R²And R³4,5,6,7,8 yuan of carbocylic radicals or virtues are formed together with the atom being connected with them Base, described carbocylic radical or aryl are by one or more R^xGroup optionally replaces.

In certain embodiments, R²For H, C_1-6Alkyl, C_2-12Thiazolinyl, C_2-12Alkynyl, carbocylic radical, aryl, heteroaryl, halogen Dai Ji ,-CN ,-SR^a、-N(R^v)₂With-CO₂R^a, any of which C_1-6Alkyl, carbocylic radical and aryl by one or more independently Selected from C_1-3Alkyl, carbocylic radical, halogeno-group ,-CN ,-N (R^v)-C(O)-R^vWith-O-R^vGroup optionally replace.

In certain embodiments, R²For H, isopropyl, ethyl, the tert-butyl group, 2,2-bis-fluoro ethyl, cyclobutyl, 2-propine- 1-base, bromine, chlorine, 2-furyl, vinyl, phenyl, 2-chlorophenylsulfanyl, 2-fluoro ethyl, 2-acrylic, 1-ethylene methacrylic basic ring third Base, 4-pyridine radicals, 2-butylene-1-base, iodine, 1-methyl-2-propine-1-base, 1-methyl-prop-1-base, 1-(cyclopropyl) ethyl, first Epoxide carbonyl, 2-butyne base, 2-hydroxyl-1-Methylethyl, 4-(mentioned methylcarbonylamino) butyl, 3-(mentioned methylcarbonylamino) third Base, 4-aminobutyl, 1-methyl-2-acrylic, 1-methyl-cyclobutyl, propyl group, 2-methoxy ethyl and 2-methyl-propyl.

In certain embodiments, R³For H.

In certain embodiments, R³For C_1–12Alkyl, C_2–12Thiazolinyl, C_2–12Alkynyl, carbocylic radical, aryl, heterocyclic radical, miscellaneous Aryl, halogeno-group ,-OR^a、-SR^a、-N(R^a)₂、-CN、-NO₂、-C(O)R^a、-CO₂R^a、-C(O)N(R^a)₂、-C(O)SR^a、-C(O)C (O)R^a、-C(O)CH₂C(O)R^a、-C(S)N(R^a)₂、-C(S)OR^a、-S(O)R^a、-SO₂R^a、-SO₂N(R^a)₂、-N(R^a)C(O)R^a、- N(R^a)C(O)N(R^a)₂、-N(R^a)SO₂R^a、-N(R^a)SO₂N(R^a)₂、-N(R^a)N(R^a)₂、-N(R^a) C (=N (R^a))N(R^a)₂、-C (=N) N (R^a)₂,-C=NOR^a,-C (=N (R^a))N(R^a)₂、-OC(O)R^aOr-OC (O) N (R^a)₂, wherein R³C_1–12Alkyl, C_2–12Thiazolinyl, C_2–12Alkynyl, carbocylic radical, aryl, heteroaryl and heterocyclic radical are each by one or more R^xGroup is individually optionally Replace.

In certain embodiments, R³For H, C_1-12Alkyl, C_2-12Thiazolinyl, C_2-12Alkynyl, aryl, heterocyclic radical, heteroaryl, Halogeno-group ,-OR^a、-N(R^a)₂、-C(O)R^a、-CO₂R^a、-C(O)N(R^a)₂Or-N (R^a)C(O)R^a, wherein R³C_1-12Alkyl, C_2-12Thiazolinyl, C_2-12Alkynyl, aryl, heteroaryl and heterocyclic radical are each by one or more R^xGroup replaces individually optionally.

In certain embodiments, R³For H, methyl, chlorine, bromine, carboxyl, formoxyl, amino carbonyl, furan-3-base, benzene Base, benzyl, phenethyl, phenoxy group, 1H-pyrazoles-4-base, 1-(Cvclopropvlmethvl)-1H-pyrazoles-4-base, 1-(1-methyl ring third Base)-1H-pyrazoles-4-base, 5-fluoro-1H-pyrazoles-4-base, 1-(2-phenyl acrylate-2-yl)-1H-pyrazoles-4-base, 1-(pyridine-3- Base)-1H-pyrazoles-4-base, 1-(pyridin-4-yl)-1H-pyrazoles-4-base, 1-(pyridine-2-base)-1H-pyrazoles-4-base, 1-[1- (N-methylaminocarbonyl)-1,1-dimethyl methyl]-1H-pyrazoles-4-base, 5-fluoro-1-isopropyl-1H-pyrazoles-4-base, 1- (Cvclopropvlmethvl)-1H-pyrazoles-5-base, 1-(Cvclopropvlmethvl)-1H-pyrazole-3-yl, 1-(tetrahydrochysene-2H-thiapyran-4-base)- 1H-pyrazoles-4-base, 1-(1,1-dioxidotetrahydro-2H-thiapyran-4-base)-1H-pyrazoles-4-base, 1-((6-(3-oxo but-1-ene- 1-yl) pyridine-2-base) methyl)-1H-pyrazoles-4-base, 3-iodophenyl, methylaminocarbonyl, 3-methyl isophthalic acid, 2,4-diazole- 5-base, 5-methyl isophthalic acid, 3,4-diazole-2-base, 1H-imidazoles-2-base, N-(benzoylmethyl) amino carbonyl, 5-phenyl Azoles-2-base, 1-cyclohexyl pyrazoles-4-base, 1-isopropylpyrazol-4-base, xenyl-3-base, 3-((4-fluorophenyl) amino) benzene Base, 3-(2-oxo-pyrrolidine-1-base) phenyl, 3-(mentioned methylcarbonylamino)-5-phenyl, phenyl amino, piperidin-1-yl, Methoxy, ethoxyl methyl, ethoxy carbonyl, 3-methoxy-propyl, benzyloxycarbonyl group, trifluoromethyl, 3-furyl, ethyl Amino carbonyl, methylol, 3-hydroxypropyl, 2-ethoxy, Methylaminomethyl, benzofuran-3-base, 1-phenyl-1H-pyrazoles- 3-base, 5-cyclopropyl furan-2-base, 2-methylfuran-3-base, 1-phenyl-1H-pyrazoles-4-base, 1-ethyl-1H-pyrazoles-4- Base, 1-methyl-6-oxo-1,6-dihydropyridine-3-base, furan-2-base, 5-benzofurane-2-base, 1-isopropyl-1H-pyrrole Azoles-4-base, pyrimidine-5-base, 5-picoline-3-base, 1-methyl isophthalic acid H-pyrazole-3-yl, 4-benzofurane-2-base, 2-fluorobenzene Base, 4-cyano-phenyl, 4-methoxyphenyl, 4-(trifluoromethyl) phenyl, 4-fluorophenyl, 1-benzyl-1H-pyrazoles-4-base, 5-chlorine Pyridin-3-yl, 5-fluorine pyridin-3-yl, acrylate-1-alkene-2-base, vinyl, 1-methyl isophthalic acid H-pyrazoles-5-base, 4-(methylol) furan Mutter-2-base, 3-cyano-phenyl, 1H-pyrazoles-5-base, 2,5-dihydrofuran-3-base, thiene-3-yl, thiophene-2-base, 1-methyl- 1H-pyrazoles-4-base, 5-methylfuran-2-base, 5-(methylol) furan-2-base, 3-(trifluoromethyl) phenyl, 3-methoxybenzene Base, 3-fluorophenyl, pyridin-3-yl, 1-(methyl sulphonyl)-1H-pyrazoles-4-base, 1-cyclopenta-1H-pyrazoles-4-base, 1-(thiophene Fen-3-ylmethyl)-1H-pyrazoles-4-base, the chloro-3-of 4-(morpholine-4-carbonyl) phenyl, 3-chloro-4-(cyclopropylaminocarbonyl) benzene Base, 1-(1-hydroxy-2-methyl acrylate-2-yl)-1H-pyrazoles-4-base, 1-(3-methoxy-benzyl)-1H-pyrazoles-4 base, 1-(pyrrole Pyridine-4-ylmethyl)-1H-pyrazoles-4-base, 1-(2-chlorobenzyl)-1H-pyrazoles-4-base, 1-(3-phenoxy benzyl)-1H-pyrazoles- 4-base, 1-(4-phenoxy benzyl)-1H-pyrazoles-4-base, 1-cyclohexyl-1H-pyrazoles-4-base, 1-(1-phenylethyl)-1H-pyrrole Azoles-4-base, 1-cyclobutyl-1H-pyrazoles-4-base, 1-(sec-butyl)-1H-pyrazoles-4-base, the fluoro-3-of 4-(pyrrolidine-1-carbonyl) Phenyl, 1-(Cyclopropylsulfonyl)-1H-pyrazole-3-yl, 1-(cyclopropane carbonyl)-1H-pyrazole-3-yl, 1-(2-cyclopropyl second Base)-1H-pyrazoles-4-base, 1-([1,1'-xenyl]-3-ylmethyl)-1H-pyrazoles-4-base, 1-phenethyl-1H-pyrazoles-4- Base, 1-(2 methoxy-benzyl)-1H-pyrazoles-4-base, 1-(4-methoxy-benzyl)-1H-pyrazoles-4-base, 1-(tert-butyl group)-1H- Pyrazoles-4-base, 3,4-3,5-dimethylphenyl, 3-chloro-4-ethoxyl phenenyl, 4-methoxyl group-3-aminomethyl phenyl, 2-methyl benzo [d] Thiazole-5-base, 1-(2-phenoxy benzyl)-1H-pyrazoles-4-base, 1-(phenyl sulfonyl)-1H-pyrazoles-4-base, 1-benzoyl Base-1H-pyrazoles-4-base, 1-benzhydryl-1H-pyrazoles-4-base, 1-([1,1'-xenyl]-2-ylmethyl)-1H-pyrazoles-4- Base, 1-(cyclohexyl methyl)-1H-pyrazoles-4-base, 1-(pyridin-3-yl methyl)-1H-pyrazoles-4-base, benzofuran-2-base, (E)-styryl, 5-ethyl furan-2-base, 1-(2-methoxy ethyl)-1H-pyrazoles-4-base, 1-(naphthalene-1-ylmethyl)- 1H-pyrazoles-4-base, 1-([1,1'-xenyl]-4-ylmethyl)-1H-pyrazoles-4-base, 3-Phenoxyphenyl, phenylene-ethynylene, 3,4-Dichlorobenzene base, 3-chloro-4-methoxy phenyl, 3-methoxyl group-4-aminomethyl phenyl, 1-(thiazole-4-yl methyl)-1H-pyrazoles- 4-base, 1H-indazole-5-base, 3,4-Dimethoxyphenyl, 4-methoxyl group-3,5-3,5-dimethylphenyl, 1-(oxetanes-3- Base)-1H-pyrazoles-4-base, 1-(2-luorobenzyl)-1H-pyrazoles-4-base, 1-(4-luorobenzyl)-1H-pyrazoles-4-base, 1-(methoxy Base carbonvlmethyl)-1H-pyrazoles-4-base, 1-(2-(dimethylamino) ethyl)-1H-pyrazoles-4-base, 3-cyano group-4-methylbenzene Base, benzo [d] [1,3] dioxole-5-base, 2,3-Dihydrobenzofuranes-5-base, 1-(3-luorobenzyl)-1H-pyrrole Azoles-4-base, 1-(thiophene-2-ylmethyl)-1H-pyrazoles-4-base, 1-(2,2,2-trifluoroethyl)-1H-pyrazoles-4-base, 1-(3- Chlorobenzyl)-1H-pyrazoles-4-base, 1-isobutyl group-1H-pyrazoles-4-base, 1-(3,3,3-trifluoro propyl)-1H-pyrazoles-4-base, 1- (difluoromethyl)-1H-pyrazoles-4-base, 1-(2-cyano ethyl)-1H-pyrazoles-4-base, 4-cyclopropyl furan-2-base, 1H-pyrrole Cough up-3-base, 2,2-difluoro benzo [d] [1,3] dioxole-5-base, 3-fluoro-4-(amino carbonyl) phenyl, the fluoro-4-of 3- (methyl sulphonyl) phenyl, 3-chloro-4-(trifluoromethoxy) phenyl, 5-fluoro-3-(amino carbonyl) phenyl, 3-(methylol)-4- Methoxyphenyl, 1-(methyl sulphonyl)-1H-pyrroles's-3-base, 1-methyl isophthalic acid H-pyrroles's-3-base, 1H-indole-2-base, ring third Base carbonylamino, benzoyl-amido, 3-bromophenyl, 3-(1-methyl-pyrazol-4-yl) phenyl, 3-(1-isopropylpyrazol-4- Base) phenyl, 4-phenyl, 4-(4-fluoroanilino) phenyl, 3-(tertbutyloxycarbonylamino) phenyl, 1-acetyl group-1,2, 3,6-tetrahydropyridine-4-base, 1-propiono-1,2,3,6-tetrahydropyridine-4-base, 1-acryloyl group-1,2,3,6-tetrahydropyridine- 4-base, 1-methyl isophthalic acid, 2,3,6-tetrahydropyridine-4-base, 1-((2-methylthiazol-4-base) methyl)-1H-pyrazoles-4-base, 1- (2-(acetyl-amino) ethyl)-1H-pyrazoles-4-base, 3,5-Dichlorobenzene base, 2-fluoro-4-(methyl sulphonyl) phenyl, 1-(uncle Amyl group)-1H-pyrazoles-4-base, 3-(2-morpholinoethyl) phenyl, 3-(2-(dimethylamino) ethyl) phenyl, 1-(1-(thiophene Azoles-4-base) ethyl)-1H-pyrazoles-4-base, 1-(tetrahydrochysene-2H-pyrans-4-base)-1H-pyrazoles-4-base, 3-methoxyl group-4-(three Methyl fluoride) phenyl, 3-methoxycarbonyl-4-chlorphenyl, 4-(trifluoromethoxy) phenyl, 3-methyl-4-(trifluoromethoxy) benzene Base, 4-cyclopropyl-3-(trifluoromethyl) phenyl, 2,2-dimethyl-2,3-Dihydrobenzofuranes-5-base, 3,5-dimethoxy benzene Base, 3,4-difluorophenyl, 4-xenyl, 3-chloro-5-fluorophenyl, 3,5-double (trifluoromethyl) phenyl, 3-fluoro-5-methoxybenzene Base, 3-(amino carbonyl) phenyl, 4-(cyclo propyl methoxy) phenyl, 2-fluoro-5-(benzyloxycarbonyl) phenyl, 3-(1H-pyrazoles- 1-yl) phenyl, 1-(2-hydroxycyclopent base)-1H-pyrazoles-4-base, 3-(N-methylaminosulfonyl) phenyl, 4-(2-hydroxyl acrylate- 2-yl) phenyl, 2-(trifluoromethyl) pyridin-4-yl, 6-phenoxypyridines-3-base, 2-methoxypyridine-4-base, 4-methyl-2- Phenyl thiazole-5-base, 3-amino-5-cyano phenyl, 1-(oxolane-3-base, 3-(N-ethyl aminocarbonyl) phenyl, 3-(ammonia Base carbonvlmethyl) phenyl, 6-phenylpyridine-3-base, 1-(tetrahydrochysene-2H-pyrans-3-base)-1H-pyrazoles-4-base, 1-(1-methoxy Base acrylate-2-yl)-1H-pyrazoles-4-base, 1-(2-ethoxyethyl group)-1H-pyrazoles-4-base, 1-acetyl group-2,5-dihydro-1H-pyrrole Cough up-3-base, 1-acetyl group-1,2,5,6-tetrahydropyridine-3-base, 1-propiono-1,2,5,6-tetrahydropyridine-3-base, 1-propionyl Base-2,5-dihydro-1H-pyrroles's-3-base, 1-((1S, 3S)-3-hydroxycyclobutyl)-1H-pyrazoles-4-base, 2,5-dihydro-1H-pyrrole Cough up-3-base, 1,2,5,6-tetrahydropyridine-3-base, 1-methyl isophthalic acid, 2,5,6-tetrahydropyridine-3-base, 1-acryloyl group-1,2,5, 6-tetrahydropyridine-3-base, 1-acryloyl group-2,5-dihydro-1H-pyrroles's-3-base, 4-chloro-3,5-3,5-dimethylphenyl, 4-cyano group- 3-aminomethyl phenyl, 1-oxo-2,3-dihydro-1H-indenes-5-base, 3,4-double (trifluoromethyl) phenyl, 3-methyl-4-(fluoroform Base) phenyl, 1-(benzo [b] thiophene-7-ylmethyl)-1H-pyrazoles-4-base, the fluoro-3-of 4-(N-cyclohexylaminocarbonyl) phenyl, 4-morphlinophenyl, 4-(4-(tert-butoxycarbonyl) piperazine-1-base) phenyl, 3-chloro-5-aminomethyl phenyl, 3-(methyl sulphonyl) Phenyl, 4-(Methylsulfonylamino) phenyl, 4-(morpholinomethyl) phenyl, 3-morphlinophenyl, 1-(2-(vinyl carbonyl Amino) ethyl)-1H-pyrazoles-4-base, 1-(2-amino-ethyl)-1H-pyrazoles-4-base, 3-cyclopropyl-4-aminomethyl phenyl, 3-second Phenyl, 3-(methylol) phenyl, 1-(2-(tertbutyloxycarbonylamino) ethyl)-1H-pyrazoles-4-base, 3-benzene ethyoxyl Phenyl, 1,2,3,6-tetrahydropyridine-4-base, 1-(2-(vinylsulfonyl amino) ethyl)-1H-pyrazoles-4-base, 4-(phenyl Amino) phenyl, 3-methyl isophthalic acid H-pyrazoles-4-base, 4-(benzyloxy) phenyl, 3,5-difluorophenyl, 3-fluoro-5-trifluoromethylbenzene Base, 3-(ethylsulfonyl) phenyl, 3-(trifluoromethoxy) phenyl, 1-(thiazole-5-ylmethyl)-1H-pyrazoles-4-base, to first Phenyl, 4-cyclopropyl phenyl, 4-(ethylsulfonyl) phenyl, 1-(6-vinylpyridine-2-base) methyl)-1H-pyrazoles-4-base, 6-(benzyloxy) pyridin-3-yl, 1-(tert-butoxycarbonyl)-2,5-dihydro-1H-pyrroles's-3-base, 1-(2-hydroxyl-1-phenyl second Base)-1H-pyrazoles-4-base, 1-(2-cyano group-1-phenylethyl)-1H-pyrazoles-4-base, 6-cyclopropyl pyridine-3-base, 4-cyano group- 3-methoxyphenyl, 4-methoxyl group-3-(trifluoromethyl) phenyl, 4-chlorphenyl, 1-(3,4-difluorobenzyl)-1H-pyrazoles-4- Base, 4-methyl-3-(trifluoromethyl) phenyl, 4-(pyrrolidine-1-carbonyl) phenyl, 4-(isopropylaminocarbonyl) phenyl, 4-(4- Methylpiperazine-1-yl) phenyl, 3-chloro-5-cyano-phenyl, 3-(pyrrolidine-1-carbonyl) phenyl, 3-(Methylsulfonylamino first Base) phenyl, 3-(1H-pyrazoles-5-base) phenyl, 4-(methyl sulphonyl) phenyl, 4-(cyclopropylaminocarbonyl) phenyl, 1-(2- Fluoro ethyl)-1H-pyrazoles-4-base, 3-(cyclo propyl methoxy) phenyl, 3-(benzyloxy) phenyl, 3-(morpholinomethyl) phenyl, 3-(phenoxymethyl) phenyl, 1-(3-fluorophenyl)-1H-pyrazoles-4-base, 2-cyclopropylethenyl, 6-(trifluoromethyl) pyridine- 3-base, 1-(4-fluorophenyl)-1H-pyrazoles-4-base, 2,4-dimethylthiazole-5-base, 1-propyl group-1H-pyrazoles-4-base, 1-fourth Base-1H-pyrazoles-4-base, 1-(2-(phenyl amino) ethyl)-1H-pyrazoles-4-base, 4-(amino carbonyl) phenyl, 4-(N-methyl Amino carbonyl) phenyl, the fluoro-4-of 3-(N-methylaminocarbonyl) phenyl, 1-(2-(3,3-difluoro azetidine-1-base) second Base)-1H-pyrazoles-4-base, 1-(2-(3,3-difluoropyrrolidin-1 base) ethyl)-1H-pyrazoles-4-base, 1-(2-((2,2,2-tri- Fluoro ethyl) amino) ethyl)-1H-pyrazoles-4-base, 1-acrylic, 3-(mentioned methylcarbonylamino) phenyl, 4-(methyl sulphonyl ammonia Base) phenyl, 4-(morpholine-4-carbonyl) phenyl, 4-(4-Acetylpiperazine-1-base) phenyl, 1-(2,2-bis-fluoro ethyl)-1H-pyrrole Azoles-4-base, 5-isopropyl furan-2-base, 1-(3,3-Difluorocyclopentyl)-1H-pyrazoles-4-base, 1-((1S, 3R)-3-hydroxyl ring Amyl group)-1H-pyrazoles-4-base, 1-((1S, 3S)-3-hydroxycyclopent base)-1H-pyrazoles-4-yl, 3-(1H-pyrazoles-4-base) benzene Base, 5-bromine furan-2-base, 3-(phenyl amino) phenyl, 2-methylthiazol-5-base, 3-(phenylene-ethynylene) phenyl, 3-phenethyl Phenyl, 1-(3-fluorine cyclopenta)-1H-pyrazoles-4-base, 1-(1-methoxyl group-2-methyl-prop-2-base)-1H-pyrazoles-4-base, 1- (1-acryloyl group azetidine-3-base)-1H-pyrazoles-4-base, 1-(1-propiono azetidine-3-base)-1H-pyrazoles- 4-base, 6-oxo-1,6-dihydropyridine-3-base, 4-(piperazine-1-base) phenyl, 1-(1-fluoro-2-methyl-prop-2-base)-1H-pyrrole Azoles-4-base, 3-(trifluoromethyl)-1H-pyrazoles-4-base, 3,5-3,5-dimethylphenyl, 4-(morpholinosulfonyl) phenyl, 3-(4-first Base piperazine-1-carbonyl) phenyl, 3-(2-hydroxyl acrylate-2-yl) phenyl, 1-isopropyl-3-methyl isophthalic acid H-pyrazoles-4-base, 1-isopropyl Base-5-methyl isophthalic acid H-pyrazoles-4-base, 3-cyclopropyl-1H-pyrazoles-5-base, 5-methoxycarbonyl pyrroles's-3-base, 3-cyclopropyl- 1-isopropyl-1H-pyrazoles-5-base, 5-cyclopropyl-1-isopropyl-1H-pyrazole-3-yl, 1-isopropyl-5-(methoxycarbonyl) Pyrroles's-3-base, 1-methyl-3-(trifluoromethyl)-1H-pyrazoles-5-base, 1-isopropyl-1H-pyrazole-3-yl, 1-cyclopenta-5- Cyclopropyl-1H-pyrazole-3-yl, 1-cyclopenta-3-cyclopropyl-1H-pyrazoles-5-base, 1-cyclopenta-1H-pyrazole-3-yl, 1-are different Propyl group-1H-pyrazoles-5-base, 1-isopropyl-5-(N-methylaminocarbonyl) pyrroles's-3-base, 1-isopropyl-5-(N, N-dimethyl Amino carbonyl) pyrroles's-3-base, 1-(2-cyclopropylethyl)-1H-pyrazole-3-yl, 1-(2-cyclopropylethyl)-1H-pyrazoles-5- Base, 1-ethyl-1H-pyrazole-3-yl, 3-(3,3-dimethyl-2-oxo-pyrrolidine-1-base) phenyl, 3-(2-oxo-3-phenyl Pyrrolidin-1-yl) phenyl, 3-((E)-styryl) phenyl, 3-(3-cyano-phenyl) phenyl, 3-(3-(methyl sulphonyl ammonia Base) phenyl) phenyl, 3-(4-(Methylsulfonylamino) phenyl) phenyl or 3-(4-(N-methylaminosulfonyl) phenyl) benzene Base.

In certain embodiments, R³For 1H-pyrazoles-4-base, 1-(Cvclopropvlmethvl)-1H-pyrazoles-4-base, 1-(1-first Cyclopropyl)-1H-pyrazoles-4-base, 5-fluoro-1H-pyrazoles-4-base, 1-(2-phenyl acrylate-2-yl)-1H-pyrazoles-4-base, 1-(pyrrole Pyridine-3-base)-1H-pyrazoles-4-base, 1-(pyridin-4-yl)-1H-pyrazoles-4-base, 1-(pyridine-2-base)-1H-pyrazoles-4-base, 1-[1-(N-methylaminocarbonyl)-1,1-dimethyl methyl]-1H-pyrazoles-4-base, 5-fluoro-1-isopropyl-1H-pyrazoles-4- Base, 1-(Cvclopropvlmethvl)-1H-pyrazoles-5-base, 1-(Cvclopropvlmethvl)-1H-pyrazole-3-yl, 1-(tetrahydrochysene-2H-thiapyran-4- Base)-1H-pyrazoles-4-base, 1-(1,1-dioxidotetrahydro-2H-thiapyran-4-base)-1H-pyrazoles-4-base, 1-((6-(3-oxo butyl- 1-alkene-1-base) pyridine-2-base) methyl)-1H-pyrazoles-4-base, 3-iodophenyl, 3-methyl isophthalic acid, 2,4-diazole-5-base, 5-first Base-1,3,4-diazole-2-base, 1H-imidazoles-2-base, 5-phenyl azoles-2-base, 1-cyclohexyl pyrazoles-4-base, 1-isopropyl Pyrazoles-4-base, xenyl-3-base, 3-((4-fluorophenyl) amino) phenyl, 3-(2-oxo-pyrrolidine-1-base) phenyl, 3-(first Base carbonylamino)-5-phenyl, 3-furyl, benzofuran-3-base, 1-phenyl-1H-pyrazole-3-yl, 5-cyclopropyl furan Mutter-2-base, 2-methylfuran-3-base, 1-phenyl-1H-pyrazoles-4-base, 1-ethyl-1H-pyrazoles-4-base, 1-methyl-6-oxygen Generation-1,6-dihydropyridine-3-base, furan-2-base, 5-benzofurane-2-base, 1-isopropyl-1H-pyrazoles-4-base, pyrimidine-5- Base, 5-picoline-3-base, 1-methyl isophthalic acid H-pyrazole-3-yl, 4-benzofurane-2-base, 2-fluorophenyl, 4-cyano-phenyl, 4- Methoxyphenyl, 4-(trifluoromethyl)-phenyl, 4-fluorophenyl, 1-benzyl-1H-pyrazoles-4-base, 5-chloropyridine-3-base, 5-fluorine Pyridin-3-yl, 1-methyl isophthalic acid H-pyrazoles-5-base, 4-(methylol) furan-2-base, 3-cyano-phenyl, 2,5-dihydrofuran-3- Base, thiene-3-yl, thiophene-2-base, 1-methyl isophthalic acid H-pyrazoles-4-base, 5-methylfuran-2-base, 5-(methylol) furan-2- Base, 3-(trifluoromethyl)-phenyl, 3-methoxyphenyl, 3-fluorophenyl, pyridin-3-yl, 1-(methyl sulphonyl)-1H-pyrazoles- 4-base, 1-cyclopenta-1H-pyrazoles-4-base, 1-(thiene-3-yl methyl)-1H-pyrazoles-4-base, the chloro-3-of 4-(morpholine-4-carbonyl Base) phenyl, 3-chloro-4-(cyclopropylaminocarbonyl) phenyl, 1-(1-hydroxy-2-methyl acrylate-2-yl)-1H-pyrazoles-4-base, 1- (3-methoxy-benzyl)-1H-pyrazoles-4-base, 1-(pyridin-4-yl methyl)-1H-pyrazoles-4-base, 1-(2-chlorobenzyl)-1H-pyrrole Azoles-4-base, 1-(3-phenoxy benzyl)-1H-pyrazoles-4-base, 1-(4-phenoxy benzyl)-1H-pyrazoles-4-base, 1-cyclohexyl- 1H-pyrazoles-4-base, 1-(1-phenylethyl)-1H-pyrazoles-4-base, 1-cyclobutyl-1H-pyrazoles-4-base, 1-(sec-butyl)-1H- Pyrazoles-4-base, the fluoro-3-of 4-(pyrrolidine-1-carbonyl) phenyl, 1-(Cyclopropylsulfonyl)-1H-pyrazole-3-yl, 1-(cyclopropane Carbonyl)-1H-pyrazole-3-yl, 1-(2-cyclopropylethyl)-1H-pyrazoles-4-base, 1-([1,1'-xenyl]-3-ylmethyl)- 1H-pyrazoles-4-base, 1-phenethyl-1H-pyrazoles-4-base, 1-(2-methoxy-benzyl)-1H-pyrazoles-4-base, 1-(4-methoxyl group Benzyl)-1H-pyrazoles-4-base, 1-(tert-butyl group)-1H-pyrazoles-4-base, 3,4-3,5-dimethylphenyl, 3-chloro-4-ethoxyl phenenyl, 4-methoxyl group-3-aminomethyl phenyl, 2-methyl benzo [d] thiazole-5-base, 1-(2-phenoxy benzyl)-1H-pyrazoles-4-base, 1- (phenyl sulfonyl)-1H-pyrazoles-4-base, 1-benzoyl-1H-pyrazoles-4-base, 1-benzhydryl-1H-pyrazoles-4-base, 1- ([1,1'-xenyl]-2-ylmethyl)-1H-pyrazoles-4-yl, 1-(cyclohexyl methyl)-1H-pyrazoles-4-base, 1-(pyridine-3- Ylmethyl)-1H-pyrazoles-4-base, benzofuran-2-base, 5-ethyl furan-2-base, 1-(2-methoxy ethyl)-1H-pyrazoles- 4-base, 1-(naphthalene-1-ylmethyl)-1H-pyrazoles-4-base, 1-([1,1'-xenyl]-4-ylmethyl)-1H-pyrazoles-4-base, 3- Phenoxyphenyl, 3,4-Dichlorobenzene base, 3-chloro-4-methoxy phenyl, 3-methoxyl group-4-aminomethyl phenyl, 1-(thiazole-4-yl first Base)-1H-pyrazoles-4-base, 1H-indazole-5-base, 3,4-Dimethoxyphenyl, 4-methoxyl group-3,5-3,5-dimethylphenyl, 1-(oxygen Azetidine-3-base)-1H-pyrazoles-4-base, 1-(2-luorobenzyl)-1H-pyrazoles-4-base, 1-(4-luorobenzyl)-1H-pyrazoles-4- Base, 1-(Methoxycarbonylmethyl)-1H-pyrazoles-4-base, 1-(2-(dimethylamino) ethyl)-1H-pyrazoles-4-base, 3-cyanogen Base-4-aminomethyl phenyl, benzo [d] [1,3] dioxole-5-base, 2,3-Dihydrobenzofuranes-5-base, 1-(3-fluorine benzyl Base)-1H-pyrazoles-4-base, 1-(thiophene-2-ylmethyl)-1H-pyrazoles-4-base, 1-(2,2,2-trifluoroethyl)-1H-pyrazoles-4- Base, 1-(3-chlorobenzyl)-1H-pyrazoles-4-base, 1-isobutyl group-1H-pyrazoles-4-base, 1-(3,3,3-trifluoro propyl)-1H-pyrrole Azoles-4-base, 1-(difluoromethyl)-1H-pyrazoles-4-base, 1-(2-cyano ethyl)-1H-pyrazoles-4-base, 4-cyclopropyl furan-2- Base, 2,2-difluoro benzo [d] [1,3] dioxole-5-base, 3-fluoro-4-(amino carbonyl) phenyl, 3-fluoro-4-(methyl Sulfonyl) phenyl, 3-chloro-4-(trifluoromethoxy) phenyl, 5-fluoro-3-(amino carbonyl) phenyl, 3-(methylol)-4-methoxyl group Phenyl, 1-(methyl sulphonyl)-1H-pyrroles's-3-base, 1-methyl isophthalic acid H-pyrroles's-3-base, 3-bromophenyl, 3-(1-methylpyrazole- 4-yl) phenyl, 3-(1-isopropylpyrazol-4-base) phenyl, 4-phenyl, 4-(4-fluoroanilino) phenyl, 3-(tert-butoxy Carbonylamino) phenyl, 1-acetyl group-1,2,3,6-tetrahydropyridine-4-base, 1-propiono-1,2,3,6-tetrahydropyridine-4-base, 1-acryloyl group-1,2,3,6-tetrahydropyridine-4-base, 1-methyl isophthalic acid, 2,3,6-tetrahydropyridine-4-base, 1-((2-methylthiazol- 4-yl) methyl)-1H-pyrazoles-4-base, 1-(2-(acetyl-amino) ethyl)-1H-pyrazoles-4-base, 3,5-Dichlorobenzene base, 2- Fluoro-4-(methyl sulphonyl) phenyl, 1-(tertiary pentyl)-1H-pyrazoles-4-base, 3-(2-morpholinoethyl) phenyl, 3-(2-(diformazan Base amino) ethyl) phenyl, 1-(1-(thiazole-4-yl) ethyl)-1H-pyrazoles-4-base, 1-(tetrahydrochysene-2H-pyrans-4-base)-1H- Pyrazoles-4-base, 3-methoxyl group-4-(trifluoromethyl) phenyl, 3-methoxycarbonyl-4-chlorphenyl, 4-(trifluoromethoxy) phenyl, 3-methyl-4-(trifluoromethoxy) phenyl, 4-cyclopropyl-3-(trifluoromethyl) phenyl, 2,2-dimethyl-2,3-dihydrobenzo furan Mutter-5-base, 3,5-Dimethoxyphenyl, 3,4-difluorophenyl, 4-xenyl, 3-chloro-5-fluorophenyl, 3,5-double (trifluoromethyl) Phenyl, 3-fluoro-5-methoxyphenyl, 3-(amino carbonyl) phenyl, 4-(cyclo propyl methoxy) phenyl, 2-fluoro-5-(benzyloxy carbonyl Base) phenyl, 3-(1H-pyrazol-1-yl) phenyl, 1-(2-hydroxycyclopent base)-1H-pyrazoles-4-base, 3-(N-methylamino sulphonyl Base) phenyl, 4-(2-hydroxyl acrylate-2-yl) phenyl, 2-(trifluoromethyl) pyridin-4-yl, 6-phenoxypyridines-3-base, 2-methoxy Yl pyridines-4-base, 4-methyl-2-phenyl thiazole-5-base, 3-amino-5-cyano phenyl, 1-(oxolane-3-base, 3-(N-second Base amino carbonyl) phenyl, 3-(amino carbonyl methyl) phenyl, 6-phenylpyridine-3-base, 1-(tetrahydrochysene-2H-pyrans-3-base)- 1H-pyrazoles-4-base, 1-(1-methoxy propyl-2-base)-1H-pyrazoles-4-base, 1-(2-ethoxyethyl group)-1H-pyrazoles-4-base, 1-acetyl group-2,5-dihydro-1H-pyrroles's-3-base, 1-acetyl group-1,2,5,6-tetrahydropyridine-3-base, 1-propiono-1,2,5, 6-tetrahydropyridine-3-base, 1-propiono-2,5-dihydro-1 h-pyrazole-3-yl, 1-((1S, 3S)-3-hydroxycyclobutyl)-1H-pyrrole Azoles-4-base, 2,5-dihydro-1H-pyrroles's-3-base, 1,2,5,6-tetrahydropyridine-3-base, 1-methyl isophthalic acid, 2,5,6-tetrahydropyridine- 3-base, 1-acryloyl group-1,2,5,6-tetrahydropyridine-3-base, 1-acryloyl group-2,5-dihydro-1H-pyrroles's-3-base, 4-are chloro- 3,5-3,5-dimethylphenyl, 4-cyano group-3-aminomethyl phenyl, 1-oxo-2,3-dihydro-1H-indenes-5-base, 3,4-are double (trifluoromethyl) Phenyl, 3-methyl-4-(trifluoromethyl) phenyl, 1-(benzo [b] thiophene-7-ylmethyl)-1H-pyrazoles-4-base, 4-fluoro-3-(N- Cyclohexylaminocarbonyl) phenyl, 4-morphlinophenyl, 4-(4-(tert-butoxycarbonyl) piperazine-1-base) phenyl, 3-chloro-5-first Base phenyl, 3-(methyl sulphonyl) phenyl, 4-(Methylsulfonylamino)-phenyl, 4-(morpholinomethyl) phenyl, 3-morpholino Phenyl, 1-(2-(ethenylcarbonylamino) ethyl)-1H-pyrazoles-4-base, 1-(2-amino-ethyl)-1H-pyrazoles-4-base, 3-ring Propyl group-4-aminomethyl phenyl, 3-ethoxyl phenenyl, 3-(methylol) phenyl, 1-(2-(tertbutyloxycarbonylamino) ethyl)-1H- Pyrazoles-4-base, 3-benzene ethoxyl phenenyl, 1,2,3,6-tetrahydropyridine-4-base, 1-(2-(vinylsulfonyl amino) ethyl)- 1H-pyrazoles-4-base, 4-(phenyl amino) phenyl, 3-methyl isophthalic acid H-pyrazoles-4-base, 4-(benzyloxy) phenyl, 3,5-difluorobenzene Base, 3-fluoro-5-trifluoromethyl, 3-(ethylsulfonyl) phenyl, 3-(trifluoromethoxy)-phenyl, 1-(thiazole-5-Ji Jia Base)-1H-pyrazoles-4-base, p-methylphenyl, 4-cyclopropyl phenyl, 4-(ethylsulfonyl)-phenyl, 1-(6-vinylpyridine-2- Base) methyl)-1H-pyrazoles-4-base, 6-(benzyloxy) pyridin-3-yl, 1-(tert-butoxycarbonyl)-2,5-dihydro-1H-pyrroles- 3-base, 1-(2-hydroxyl-1-phenylethyl)-1H-pyrazoles-4-base, 1-(2 cyano group-1-phenylethyl)-1H-pyrazoles-4-base, 6- Cyclopropyl pyridine-3-base, 4-cyano group-3-methoxyphenyl, 4-methoxyl group-3-(trifluoromethyl) phenyl, 4-chlorphenyl, 1-(3, 4-difluorobenzyl)-1H-pyrazoles-4-base, 4-methyl-3-(trifluoromethyl) phenyl, 4-(pyrrolidine-1-carbonyl) phenyl, 4-be (different Propylcarbamic-carbonyl) phenyl, 4-(4-methylpiperazine-1-yl) phenyl, 3-chloro-5-cyano-phenyl, 3-(pyrrolidine-1-carbonyl) Phenyl, 3-(Methylsulfonylamino methyl) phenyl, 3-(1H-pyrazoles-5-base) phenyl, 4-(methyl sulphonyl) phenyl, 4-(ring Propylaminocarbonyl) phenyl, 1-(2-fluoro ethyl)-1H-pyrazoles-4-base, 3-(cyclo propyl methoxy) phenyl, 3-(benzyloxy) benzene Base, 3-(morpholinomethyl) phenyl, 3-(phenoxymethyl) phenyl, 1-(3-fluorophenyl)-1H-pyrazoles-4-base, 2-cyclopropyl second Thiazolinyl, 6-(trifluoromethyl) pyridin-3-yl, 1-(4-fluorophenyl)-1H-pyrazoles-4-base, 2,4-dimethylthiazole-5-base, 1-third Base-1H-pyrazoles-4-base, 1-butyl-1H-pyrazoles-4-base, 1-(2-(phenyl amino) ethyl)-1H-pyrazoles-4-base, 4-(amino Carbonyl) phenyl, 4-(N-methylaminocarbonyl) phenyl, the fluoro-4-of 3-(N-methylamino-carbonyl) phenyl, 1-(2-(3,3-difluoro Azetidine-1-base) ethyl)-1H-pyrazoles-4-base, 1-(2-(3,3-difluoropyrrolidin-1 base) ethyl)-1H-pyrazoles-4- Base, 1-(2-((2,2,2-trifluoroethyl) amino) ethyl)-1H-pyrazoles-4-base, 1-acrylic, 3-(mentioned methylcarbonylamino) benzene Base, 4-(Methylsulfonylamino) phenyl, 4-(morpholine-4-carbonyl) phenyl, 4-(4-Acetylpiperazine-1-base) phenyl, 1-(2, 2-bis-fluoro ethyl)-1H-pyrazoles-4-base, 5-isopropyl furan-2-base, 1-(3,3-Difluorocyclopentyl)-1H-pyrazoles-4-base, 1- ((1S, 3R)-3-hydroxycyclopent base)-1H-pyrazoles-4-base, 1-((1S, 3S)-3-hydroxycyclopent base)-1H-pyrazoles-4-yl, 3- (1H-pyrazoles-4-base) phenyl, 5-bromine furan-2-base, 3-(phenyl amino) phenyl, 2-methylthiazol-5-base, 3-(phenylacetylene Base) phenyl, 3-phenethyl phenyl, 1-(3-fluorine cyclopenta)-1H-pyrazoles-4-base, 1-(1-methoxyl group-2-methyl-prop-2-base)- 1H-pyrazoles-4-base, 1-(1-acryloyl group azetidine-3-base)-1H-pyrazoles-4-base, 1-(1-propiono azetidin Alkane-3-base)-1H-pyrazoles-4-base, 6-oxo-1,6-dihydropyridine-3-base, 4-(piperazine-1-base) phenyl, 1-(1-fluoro-2-first Base acrylate-2-yl)-1H-pyrazoles-4-base, 3-(trifluoromethyl)-1H-pyrazoles-4-base, 3,5-3,5-dimethylphenyl, 4-(morpholino sulphur Acyl group) phenyl, 3-(4-methyl piperazine-1-carbonyl) phenyl, 3-(2-hydroxyl acrylate-2-yl) phenyl, 1-isopropyl-3-methyl isophthalic acid H- Pyrazoles-4-base, 1-isopropyl-5-methyl isophthalic acid H-pyrazoles-4-base, 3-cyclopropyl-1H-pyrazoles-5-base, 5-methoxycarbonyl pyrrole Cough up-3-base, 3-cyclopropyl-1-isopropyl-1H-pyrazoles-5-base, 5-cyclopropyl-1-isopropyl-1H-pyrazole-3-yl, 1-isopropyl Base-5-(methoxycarbonyl) pyrroles-3-base, 1-methyl-3-(trifluoromethyl)-1H-pyrazoles-5-base, 1-isopropyl-1H-pyrazoles- 3-base, 1-cyclopenta-5-cyclopropyl-1H-pyrazole-3-yl, 1-cyclopenta-3-cyclopropyl-1H-pyrazoles-5-base, 1-cyclopenta- 1H-pyrazole-3-yl, 1-isopropyl-1H-pyrazoles-5-base, 1-isopropyl-5-(N-methylaminocarbonyl) pyrroles's-3-base, 1-are different Propyl group-5-(N, N-Dimethylaminocarbonyl) pyrroles's-3-base, 1-(2-cyclopropylethyl)-1H-pyrazole-3-yl, 1-(2-ring third Base ethyl)-1H-pyrazoles-5-base, 1-ethyl-1H-pyrazole-3-yl, 3-(3,3-dimethyl-2-oxo-pyrrolidine-1-base) benzene Base, 3-(2-oxo-3-Phenylpyrrolidine-1-base) phenyl, 3-((E)-styryl) phenyl, 3-(3-cyano-phenyl) phenyl, 3-(3-(Methylsulfonylamino) phenyl) phenyl, 3-(4-(Methylsulfonylamino) phenyl) phenyl or 3-(4-(N-methyl ammonia Base sulfonyl) phenyl) phenyl.

In certain embodiments, R³For aryl or heteroaryl, wherein aryl and heteroaryl are each by one or more R^xBase Group optionally replaces, and condition is R³It not phenyl, fluorophenyl, chlorphenyl, pyridine radicals, nitrobenzophenone or propyl group isoxazole.

In certain embodiments, R³For pyrazoles-4-base, it is by R^XOptionally replace.

In certain embodiments, R^xFor by one or more C replaced independently selected from following group_1-6Alkyl: R^xa, oxo base, halogeno-group ,-NO₂、-N(R^v)₂、-CN、-C(O)-N(R^v)₂、-S(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-O- R^v、-S-R^v、-O-C(O)-R^v、-C(O)-R^v、-C(O)-O-R^v、-S(O)-R^v、-S(O)₂-R^v、-C(O)-N(R^v)₂、-S(O)₂-N (R^v)₂、-N(R^v)-C(O)-R^v、N(R^v)-C(O)-OR^v、-N(R^v)-S(O)-R^vAnd-N (R^v)-S(O)₂-R^v。

In certain embodiments, R^xFor by R^xaOptionally substituted C_1-6Alkyl.

In certain embodiments, R³For by R^xSubstituted pyrazoles-4-base.

In certain embodiments, R³For by oxo base, C_1-6Alkyl, C_2-6Thiazolinyl, C_2-6Alkynyl, carbocylic radical, aryl, miscellaneous Aryl, heterocycle ,-N (R^v)₂、-CN、-C(O)-N(R^v)₂、-S(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-O-R^v、-S-R^v、-O-C (O)-R^v、-O-C(O)-O-R^v、-C(O)-R^v、-C(O)-O-R^v、-S(O)-R^v、-S(O)₂-R^v、-O-C(O)-N(R^v)₂、-N (R^v)-C(O)-OR^v、-N(R^v)-C(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-N(R^v)-C(O)-R^v、-N(R^v)-S(O)-R^v、-N (R^v)-S(O)₂R^v、-N(R^v)-S(O)-N(R^v)₂Or-N (R^v)-S(O)₂-N(R^v)₂Substituted phenyl, any of which C_1-6Alkane Base, C_2-6Thiazolinyl, C_2-6Alkynyl, carbocylic radical, aryl, heteroaryl and heterocyclic radical by one or more independently selected from R^xa, oxo base, Halogeno-group ,-NO₂、-N(R^v)₂、-CN、-C(O)-N(R^v)₂、-S(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-O-R^v、-S-R^v、-O-C (O)-R^v、-C(O)-R^v、-C(O)-O-R^v、-S(O)-R^v、-S(O)₂-R^v、-C(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-N(R^v)-C (O)-R^v、-N(R^v)-C(O)-OR^v、-N(R^v)-S(O)-R^v、-N(R^v)-S(O)₂-R^vOr C_1-6Alkyl (its by one or more solely On the spot the group selected from oxo base and halogeno-group optionally replaces) group optionally replaces.

In certain embodiments, R^xFor C_2-6Thiazolinyl or C_2-6Alkynyl, any of which C_2-6Thiazolinyl and C_2-6Alkynyl is by one Individual or multiple optionally replace independently selected from following group: R^xa, oxo base, halogeno-group ,-NO₂、-N(R^v)₂、-CN、-C (O)-N(R^v)₂、-S(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-O-R^v、-S-R^v、-O-C(O)-R^v、-C(O)-R^v、-C(O)-O- R^v、-S(O)-R^v、-S(O)₂-R^v、-C(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-N(R^v)-C(O)-R^v、N(R^v)-C(O)-OR^v、-N (R^v)-S(O)-R^vAnd-N (R^v)-S(O)₂-R^v。

In certain embodiments, R^xSelected from C_2-6Thiazolinyl, C_2-6Alkynyl, carbocylic radical, aryl, heteroaryl, heterocycle ,-F ,- Cl、-Br、-I、-NO₂、-N(R^v)₂、-CN、-C(O)-N(R^v)₂、-S(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-O-R^v、-S-R^v、- O-C(O)-R^v、-O-C(O)-O-R^v、-C(O)-R^v、-C(O)-O-R^v、-S(O)-R^v、-S(O)₂-R^v、-O-C(O)-N(R^v)₂,、-N (R^v)-C(O)-OR^v、-N(R^v)-C(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-N(R^v)-C(O)-R^v、-N(R^v)-S(O)-R^v、-N (R^v)S(O₂)R^v、-N(R^v)-S(O)-N(R^v)₂And-N (R^v)-S(O)₂-N(R^v)₂, any of which C_2-6Thiazolinyl, C_2-6Alkynyl, Carbocylic radical, aryl, heteroaryl and heterocyclic radical are optionally replaced independently selected from following group by one or more: R^xa, oxo Base, halogeno-group ,-NO₂、-N(R^v)₂、-CN、-C(O)-N(R^v)₂、-S(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-O-R^v、-S-R^v、- O-C(O)-R^v、-C(O)-R^v、-C(O)-O-R^v、-S(O)-R^v、-S(O)₂-R^v、-C(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-N (R^v)-C(O)-R^v、N(R^v)-C(O)-OR^v、-N(R^v)-S(O)-R^v、-N(R^v)-S(O)₂-R^vAnd C_1-6Alkyl (its by one or Multiple groups independently selected from oxo base and halogeno-group optionally replace).

In certain embodiments, R³For by oxo base, C_1-6Alkyl, C_2-6Thiazolinyl, C_2-6Alkynyl, carbocylic radical, aryl, miscellaneous Aryl, heterocycle ,-F ,-Cl ,-Br ,-I ,-NO₂、-N(R^v)₂、-CN、-C(O)-N(R^v)₂、-S(O)-N(R^v)₂、-S(O)₂-N (R^v)₂、-O-R^v、-S-R^v、-O-C(O)-R^v、-O-C(O)-O-R^v、-C(O)-R^v、-C(O)-O-R^v、-S(O)-R^v、-S(O)₂- R^v、-O-C(O)-N(R^v)₂、-N(R^v)-C(O)-OR^v、-N(R^v)-C(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-N(R^v)-C(O)- R^v、-N(R^v)-S(O)-R^v、-N(R^v)-S(O)₂-R^v、-N(R^v)-S(O)-N(R^v)₂Or-N (R^v)-S(O)₂-N(R^v)₂Substituted miscellaneous Aryl；Any of which C_1–6Alkyl by one or more independently selected from R^xa, oxo base, halogeno-group ,-NO₂、-N(R^v)₂、- CN、-C(O)-N(R^v)₂、-S(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-O-R^v、-S-R^v、-O-C(O)-R^v、-C(O)-R^v、-C(O)- O-R^v、-S(O)-R^v、-S(O)₂-R^v、-C(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-N(R^v)-C(O)-R^v、-N(R^v)-C(O)- OR^v、-N(R^v)-S(O)-R^vAnd-N (R^v)-S(O)₂-R^vGroup optionally substituted；And any of which C_2-6Thiazolinyl, C_2–6Alkynes Base, carbocylic radical, aryl, heteroaryl and heterocyclic radical by one or more independently selected from R^xa, oxo base, halogeno-group ,-NO₂、-N (R^v)₂、-CN、-C(O)-N(R^v)₂、-S(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-O-R^v、-S-R^v、-O-C(O)-R^v、-C(O)- R^v、-C(O)-O-R^v、-S(O)-R^v、-S(O)₂-R^v、-C(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-N(R^v)-C(O)-R^v、-N (R^v)-C(O)-OR^v、-N(R^v)-S(O)-R^v、-N(R^v)-S(O)₂-R^vAnd C_1-6(it is selected independently alkyl by one or more Optionally replace from the group of oxo base and halogeno-group) group optionally replace.

In certain embodiments, R³For by oxo base, C_1-6Alkyl, C_2-6Thiazolinyl, C_2-6Alkynyl, carbocylic radical, aryl, miscellaneous Aryl, heterocycle ,-F ,-Cl ,-Br ,-I ,-NO₂、-N(R^v)₂、-CN、-C(O)-N(R^v)₂、-S(O)-N(R^v)₂、-S(O)₂-N (R^v)₂、-O-R^v、-S-R^v、-O-C(O)-R^v、-O-C(O)-O-R^v、-C(O)-R^v、-C(O)-O-R^v、-S(O)-R^v、-S(O)₂- R^v、-O-C(O)-N(R^v)₂、-N(R^v)-C(O)-OR^v、-N(R^v)-C(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-N(R^v)-C(O)- R^v、-N(R^v)-S(O)-R^v、-N(R^v)-S(O)₂-R^v、-N(R^v)-S(O)-N(R^v)₂Or-N (R^v)-S(O)₂-N(R^v)₂Substituted 5 Unit's heteroaryl；Any of which C_1-6Alkyl by one or more independently selected from R^xa, oxo base, halogeno-group ,-NO₂、-N (R^v)₂、-CN、-C(O)-N(R^v)₂、-S(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-O-R^v、-S-R^v、-O-C(O)-R^v、-C(O)- R^v、-C(O)-O-R^v、-S(O)-R^v、-S(O)₂-R^v、-C(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-N(R^v)-C(O)-R^v、-N (R^v)-C(O)-OR^v、-N(R^v)-S(O)-R^vAnd-N (R^v)-S(O)₂-R^vGroup replace；And any of which C_2-6Alkene Base, C_2-6Alkynyl, carbocylic radical, aryl, heteroaryl and heterocyclic radical by one or more independently selected from R^xa, oxo base, halogeno-group ,- NO₂、-N(R^v)₂、-CN、-C(O)-N(R^v)₂、-S(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-O-R^v、-S-R^v、-O-C(O)-R^v、-C (O)-R^v、-C(O)-O-R^v、-S(O)-R^v、-S(O)₂-R^v、-C(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-N(R^v)-C(O)-R^v、-N (R^v)-C(O)-OR^v、-N(R^v)-S(O)-R^v、-N(R^v)-S(O)₂-R^vAnd C_1-6Alkyl (its by one or more independently selected from The group of oxo base and halogeno-group optionally replaces) group optionally replace.

In certain embodiments, R³For by oxo base, C_1-6Alkyl, C_2-6Thiazolinyl, C_2-6Alkynyl, carbocylic radical, aryl, miscellaneous Aryl, heterocycle ,-N (R^v)₂、-CN、-C(O)-N(R^v)₂、-S(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-O-R^v、-S-R^v、-O-C (O)-R^v、-O-C(O)-O-R^v、-C(O)-R^v、-C(O)-O-R^v、-S(O)-R^v、-S(O)₂-R^v、-O-C(O)-N(R^v)₂、-N (R^v)-C(O)-OR^v、-N(R^v)-C(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-N(R^v)-C(O)-R^v、-N(R^v)-S(O)-R^v、-N (R^v)-S(O)₂-R^v、-N(R^v)-S(O)-N(R^v)₂Or-N (R^v)-S(O)₂-N(R^v)₂Substituted phenyl；Any of which C_1-6Alkane Base by one or more independently selected from R^xa, oxo base, halogeno-group ,-NO₂、-N(R^v)₂、-CN、-C(O)-N(R^v)₂、-S(O)-N (R^v)₂、-S(O)₂-N(R^v)₂、-O-R^v、-S-R^v、-O-C(O)-R^v、-C(O)-R^v、-C(O)-O-R^v、-S(O)-R^v、-S(O)₂- R^v、-C(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-N(R^v)-C(O)-R^v、-N(R^v)-C(O)-OR^v、-N(R^v)-S(O)-R^vAnd-N (R^v)-S(O)₂-R^vGroup replace；And any of which C_2-6Thiazolinyl, C_2-6Alkynyl, carbocylic radical, aryl, heteroaryl and heterocycle Base is optionally replaced independently selected from following group by one or more: R^xa, oxo base, halogeno-group ,-NO₂、-N(R^v)₂、- CN、-C(O)-N(R^v)₂、-S(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-O-R^v、-S-R^v、-O-C(O)-R^v、-C(O)-R^v、-C(O)- O-R^v、-S(O)-R^v、-S(O)₂-R^v、-C(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-N(R^v)-C(O)-R^v、-N(R^v)-C(O)- OR^v、-N(R^v)-S(O)-R^v、-N(R^v)-S(O)₂-R^vAnd C_1-6Alkyl (its by one or more independently selected from oxo base and halogen The group of Dai Ji optionally replaces).

In certain embodiments, R²And R³Cyclohexyl ring, described cyclohexyl ring quilt is formed together with the atom being connected with them One or more R^xGroup optionally replaces.

In certain embodiments, R²And R³Forming benzyl ring together with the atom being connected with them, described benzyl ring is by one Or multiple R^xGroup optionally replaces.

In certain embodiments, R⁴For H, methyl, ethyl, propyl group, Cvclopropvlmethvl, 2-hydroxyethyl, 2-(dimethyl Amino) ethyl, phenyl, benzyl or 2-methoxy ethyl.

In certain embodiments, R⁴And R³Heterocyclic radical is formed together with the atom being connected with them.

In certain embodiments, the invention provides formula (I) compound described as any one of embodiment 1-432 Or its salt.

In certain embodiments, the invention provides formula (I) compound described as any one of embodiment 1-457 Or its salt.

In certain embodiments, described compound be not following any one:

In certain embodiments, described compound is not formula (II) compound:

Wherein:

Work as R²For ethoxy carbonyl and R³During for H, R¹For 3-(methylamino) propyl group；

Work as R²For H and R³It is 2, during 3-dihydro-Isosorbide-5-Nitrae-benzo dioxine-6-base, R¹For H；

Work as R²For H and R³During for 4-chlorphenyl, R¹For methoxyl group；

Work as R²For H and R³During for 4-chlorphenyl, R¹For hydroxyl；

Work as R²For ethyl, ethoxy carbonyl methyl, 2-hydroxypropyl, 2-(acyloxy) propyl group, 2-(acyloxy) ethyl, 2- (2-(N-Benzyoxycarbonylamino) propionyloxy) propyl group, 2-chloropropyl, 1-(ethoxy carbonyl) ethyl, ethoxy carbonyl first Base, 1-(carbonyl) ethyl, 1-(1-(dion e) ethoxy carbonyl) ethyl, 2-hydroxyl-1-Methylethyl, 2-hydroxyl second Base or 4-(trifluoromethylthio) benzyl and R³During for methyl, R¹For H；

Work as R²For H and R³For phenyl, tetrahydropyran-4-base methyl, chloromethyl, methoxycarbonyl, ethoxy carbonyl first When base, benzyl or 1-(2-fluorophenyl) cyclopropyl, R¹For H；

Work as R²For H, 4-benzyloxy-phenyl, 3,4-dihydro-6,7-dimethyl-3-oxo-2-quinoxalinyl or indole-3- Base, 3-pyrazolyl, ethoxy carbonyl, cyano group, 3,4-dihydro-3-oxo-2-quinoxalinyl or carbonyl and R³During for H, R¹For H；

Work as R²For H and R³During for trifluoromethyl, R¹For 3-amino piperidine subbase；

Work as R²For H and R³During for methyl, R¹For H, methyl, phenyl, N-(4-fluorophenyl) amino, N-phenyl amino, N-benzyl Base amino, N-(3,5-Dimethoxyphenyl) amino, N-(3-methoxyphenyl) amino, N-(4-methoxyphenyl) amino, N- (3,4-Dimethoxyphenyl) amino, N-(4-aminomethyl phenyl) amino, N-(2-methoxyphenyl) amino, 4,5,6,7-tetrahydrochysene- 1H-indole-2-base, N-(4-fluorophenyl) amino or N-(4-propyl group phenyl) amino；

Work as R²For H and R³During for isopropyl, R¹For phenyl amino；

Work as R²For H and R³During for phenyl, 2-fluorophenyl, 2-chlorphenyl or chloromethyl, R¹For N-(3,5-dimethoxy benzene Base) amino；

Work as R²For chlorine and R³During for methyl, R¹For N-(3,5-Dimethoxyphenyl) amino；

Work as R²For H and R³During for ethyl, R¹For methyl, N-(4-morphlinophenyl) amino, N-(3-methoxyl group-4-(2- Morpholino ethyoxyl) phenyl) amino, N-(3,5-Dimethoxyphenyl) amino or N-(4-propyl group phenyl) amino；

Work as R²For H and R³During for cyclopropyl, R¹For N-(3-methoxyl group-5-(2-morpholino ethyoxyl) phenyl) amino, N- (3,5-Dimethoxyphenyl) amino, phenyl amino, N-(4-bromophenyl) amino or N-(4-morphlinophenyl) amino；

Work as R²For H and R³During for isopropyl, R¹For N-(3,5-Dimethoxyphenyl) amino；

Work as R²For methyl and R³During for methyl, R¹For N-(3,5-Dimethoxyphenyl) amino；

Work as R²For fluorine and R³During for methyl, R¹For N-(3,5-Dimethoxyphenyl) amino；

Work as R²For H and R³During for methoxy, R¹For N-(3,5-Dimethoxyphenyl) amino；

Work as R²For H and R³During for Methoxycarbonylmethyl, R¹For N-(3,5-Dimethoxyphenyl) amino；

Work as R²For H and R³During for propyl group, R¹For H, methyl or N-(3,5-Dimethoxyphenyl) amino；

Work as R²For benzyl and R³During for methyl, R¹For H, methyl or N-(3,5-Dimethoxyphenyl) amino；

Work as R²For benzyl and R³During for H, R¹For H or methyl；

Work as R²For H and R³During for phenyl, 2-pyridine radicals or N, N-dimethylaminomethyl, R¹For N-(3,5-dimethoxy Phenyl) amino；

Work as R²For 2-hydroxyethyl, 2-chloroethyl, 2-(acyloxy) ethyl and R³During for ethoxy carbonyl, R¹For H；

Work as R²For 2-ethoxy and R³During for hydroxyl, R¹For H；

Work as R²For 2-(acyloxy) ethyl and R³During for benzyloxymethyl, R¹For H；

Work as R²For H and R³During for H, R¹For 2-pyrrole radicals；

Work as R²It is 3,4-dihydro-6,7-dimethyl-3-oxo-2-quinoxalinyl and R³During for H, R¹For N-(4-ethyoxyl Phenyl) amino；

Work as R²For 2-(acyloxy) ethyl and R³During for methoxy, R¹For H；

Work as R²For cyano group and R³During for phenyl or 4-chlorphenyl, R¹For H；

Work as R²For 3,4-dihydro-3-oxo-2-quinoxalinyl and R³During for H, R¹For methyl；

Work as R²And R³When formation condenses benzo ring together, R¹For H；

Work as R²For 3-methoxy-benzyl and R³During for propyl group, R¹For H；

Work as R²For H, ethyl, ethoxy carbonyl methyl or 3-chlorobenzyl and R³During for methyl, R¹For methyl；

Work as R²For H and R³During for 3-chlorobenzyl, 5-(propyl group) isoxazole-3-base or 4-nitrobenzophenone, R¹For pyrrolidine Base；

Work as R²For H and R³During for Pentamethylene oxide .-2-base, R¹For morpholino；

Work as R²For benzoyl-amido and R³During for H, R¹For pyrrolidino；

Work as R²For H and R³During for 4-nitrobenzophenone, R¹For N-(4-methoxyphenyl) amino；

Work as R²For 2-(2,4 dichloro benzene formyloxy) ethyl, 2-(3-toluyl epoxide) ethyl, 2-(acetyl oxygen Base) ethyl or 2-(cyclohexyl-carbonyl epoxide) ethyl and R³During for methyl, R¹For H；

Work as R²And R³When forming fused rings amyl group ring together, R¹For methyl；

Work as R²And R³When formation condenses cyclohexyl ring together, R¹For H；

Work as R²For H and R³During for ethoxy carbonyl methyl, R¹For methyl；

Work as R²For H and R³During for methyl or amino, R¹For phenyl；

Work as R²For chlorine and R³During for methyl, R¹For H；

R¹For methyl, R²For H, and R³For phenyl；

R¹For methyl, R²For 2-hydroxyethyl, and R³For methyl；Or

R¹For methyl mercapto, R²For H, and R³For phenyl.

In certain embodiments, described compound be not following any one:

Purposes, preparation and use

Pharmaceutically acceptable compositions

According to another embodiment, the invention provides a kind of compositions, it comprises provided compound or its medicine Acceptable derivates and pharmaceutically acceptable carrier, adjuvant or excipient on.Compound in the compositions of the present invention Amount be to be effective in the histone demethylase or the amount of its mutant measurably suppressed in biological sample or patient.One In a little embodiments, histone demethylase is 2-oxoglutaric acid dependent form enzyme.In some embodiments, histone demethylation Enzyme is the protein containing Jumonji domain.In some embodiments, histone demethylase is H3K4 (histone 3K4) demethylase family member.In certain embodiments, histone demethylase is the enzyme of JARID subtribe.Real at some Executing in scheme, histone demethylase is selected from JARID1A, JARID1B or its mutant.

In certain embodiments, in the compositions of the present invention, the amount of compound measurably suppresses at biology for being effective in 2-oxoglutaric acid dependent form enzyme in sample or patient or the amount of its mutant.In certain embodiments, 2-oxoglutaric acid depends on Relying type enzyme is the protein containing Jumonji domain.In certain embodiments, the described egg containing Jumonji domain White matter is JMJD2 subtribe member.In certain embodiments, JMJD2 subtribe member is GASC1.

In certain embodiments, in the compositions of the present invention, the amount of compound measurably suppresses at biology for being effective in H3K4 (H3 K4) the demethylase family member of protein or the amount of its mutant in sample or patient.Implement at some In scheme, in the present composition, the amount of compound is to be effective in measurably to suppress protein in biological sample or patient JARID subtribe member or the amount of its mutant.In some embodiments, in the present composition amount of compound for being effective in Measurably suppress the amount of JARID1A, the JARID1B in biological sample or patient or its mutant.

In certain embodiments, the compositions of the present invention is formulated for the trouble being administered to need this compositions Person.In some embodiments, the compositions of the present invention is formulated into and is applied orally to patient.

As used herein, term " patient " means animal, such as mammal, such as the mankind.

Term " pharmaceutically acceptable carrier, adjuvant or excipient " refers to destroy the medicine of the compound prepared with it Non-toxic carrier, adjuvant or the excipient of reason activity.Can be used for the pharmaceutically acceptable carrier of the compositions of the present invention, adjuvant or Excipient includes but not limited to: ion-exchanger, aluminium oxide, aluminium stearate, lecithin, serum albumin are (such as human seralbumin egg In vain), buffer substance (such as phosphate), glycerol, sorbic acid, potassium sorbate, the partial glyceride mixture of saturated vegetable fatty acid, Water, salt or electrolyte (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt), colloidal silica, three Magnesium silicate, polyvinylpyrrolidone, cellulose base materials, Polyethylene Glycol, sodium carboxymethyl cellulose, polyacrylate, wax, poly-second Alkene-polyoxypropylene block polymer, Polyethylene Glycol and lanoline.

" pharmaceutically acceptable derivates " mean the most nontoxic salt of the compound of the present invention, ester, ester salt or other Derivant, they can provide the compound of the present invention or its inhibitory activity after being applied to receiver directly or indirectly Metabolite or residue.

As used herein, term " metabolite of its inhibitory activity or residue " means its metabolite or residue also It it is the inhibitor of histone demethylase or its mutant.

The compositions of the present invention can be administered orally, parenteral, by suck spraying, locally, rectum, nose, cheek, vagina or via The mode implanting drug storehouse storage is used.As used herein, term " parenteral " include subcutaneous, intravenous, intramuscular, intraarticular, In intrasynovial, breastbone, in sheath, in liver, intralesional and intracranial injection or infusion techniques.

Include but not limited to for Orally administered liquid dosage form, pharmaceutically acceptable Emulsion, microemulsion, solution, mixed Suspension, syrup and elixir.In addition to reactive compound, liquid dosage form can be dilute containing the inertia generally used in the art Release agent, such as water or other solvent, lytic agent and emulsifying agent such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, Benzyl benzoate, propylene glycol, 1,3 butylene glycol, dimethylformamide, oil (especially Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, Semen Maydis oil, plumule Oil, olive oil, Oleum Ricini and Oleum sesami), glycerol, tetrahydrofurfuryl alcohol, Polyethylene Glycol and the fatty acid ester of sorbitol anhydride and mixed Compound.Besides inert diluents, Orally administered composition also can comprise adjuvant such as wetting agent, emulsifying agent and suspending agent, sweeting agent, tune Taste agent and aromatic.

Injectable formulation, such as sterile injectable aqueous or oil-based suspension can use according to known technology and suitably divide Powder or wetting agent and suspending agent are prepared.Sterile injectable preparation is alternatively at the acceptable non-toxic diluent of parenteral or solvent In sterile injectable solution, suspension or Emulsion, such as, as the solution in 1,3 butylene glycol.Adoptable acceptable Excipient and solvent are water, Ringer's mixture (U.S.P.) and isotonic sodium chlorrde solution.It addition, aseptic fixing oil is typically used as Solvent or suspension media.For this purpose, the gentleest fixing oil can be used, including monoglyceride or two glycerol of synthesis Ester.It addition, fatty acid such as oleic acid is used for preparing injectable formulation.

Injectable formulation can such as by filter via bacteria-retaining filter or before use by being dissolvable in water or The aseptic solid composite form being scattered in sterilized water or other sterile injectable medium adds biocide and carrys out sterilizing.

In order to extend the effect of the compound of the present invention, it is usually desirable to slow down from subcutaneous injection or intramuscular injection The absorption of compound.This can be realized by the liquid suspension of the crystallization of use poorly water-soluble or amorphous materials.Compound Absorption rate then depend on its rate of dissolution, and rate of dissolution can be depending on crystal size and crystal form.Alternatively, parenteral is executed The delay of compound form absorb by by compound dissolution in or be suspended in oiliness excipient and realize.Injectable stores up Storehouse formula form by biodegradable polymers such as polylactide-polyglycolide in formed compound microencapsulated matrices come Formed.Ratio according to compound and polymer and the character of particular polymers used, the release of controlled produced compounds is fast Rate.The example of other biodegradable polymers includes poly-(ortho esters) and poly-(anhydride).Reservoir type injectable formulation also can lead to Cross and can the liposome compatible with bodily tissue or microemulsion prepared encapsulation compound.

Compositions for rectum or vaginal application preferably can be by making the compound of the present invention and suitable non-stimulated Property excipient or carrier mix the suppository prepared, described excipient or carrier such as cocoa butter, Polyethylene Glycol or suppository wax, they It is solid at ambient temperature but is liquid under body temperature, and in rectum or vaginal canal, therefore melt also release of active Compound.

Solid dosage forms for oral administration includes capsule, tablet, pill, powder and granule.In these solid dosage formss In, reactive compound and at least one pharmaceutically acceptable inert excipient or carrier (such as sodium citrate or dicalcium phosphate) And/or the mixing of following material: a) filler or extender, such as starch, lactose, sucrose, glucose, mannitol and silicic acid； B) binding agent, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and arabic gum；C) protect Humectant, such as glycerol；D) disintegrating agent, such as agar, calcium carbonate, Rhizoma Solani tuber osi or tapioca, alginic acid, some silicate and carbonic acid Sodium；E) solution fire retardant, such as paraffin；F) absorption enhancer, such as quaternary ammonium compound；G) wetting agent is such as hard as hexadecanol and list Glycerol；H) adsorbent, such as Kaolin and bentonite；And i) lubricant, as Talcum, calcium stearate, magnesium stearate, Solid polyethylene glycol, sodium lauryl sulfate and mixture thereof.In the case of capsule, tablet and pill, dosage form also can comprise slow Electuary.

The solid composite of similar type is used as these excipient such as lactose (lactose) or lactose (milk And high molecular weight polyethylene glycol etc. carrys out the filler in the gelatine capsule filled as soft and hard sugar).Tablet, sugar The solid dosage forms of clothing ball, capsule, pill and granule can use coating and involucrum such as enteric coating and pharmaceutical field known its He prepares by coating.They optionally contain opacifiers and also can have only or preferably intestinal certain a part, appoint The compositions of selection of land release of active ingredients in a delayed fashion.The example of spendable embedding composition include polymeric material and Wax.The solid composite of similar type be used as these excipient such as lactose (lactose) or lactose (milk sugar) with And high molecular weight polyethylene glycol etc. carrys out the filler in the gelatine capsule filled as soft and hard.

Described reactive compound can be also the micro-encapsulated form with one or more excipient as above.Tablet, The solid dosage forms of dragee, capsule, pill and granule can use coating and involucrum such as enteric coating, release control coating and system Medicine field it is well known that other coatings prepare.In this type of solid dosage forms, reactive compound can be with at least one inert diluents Agent such as sucrose, lactose or starch mix.. this kind of dosage form according to normal operating, also can comprise besides inert diluents other Material, such as, tableting lubricant and other compression aids, such as magnesium stearate and microcrystalline Cellulose.At capsule, tablet and pill In the case of, dosage form also can comprise buffer agent.They optionally contain opacifiers and also can have only or preferably at intestinal Certain part, the compositions of release of active ingredients the most in a delayed fashion.The example of spendable embedding composition includes Polymeric material and wax.

The local of the compound of the present invention or the dosage form of applied dermally include: ointment, paste, cream, lotion, gel, dissipate Agent, solution, spray, inhalant or paster agent.Aseptically, by active component and pharmaceutically acceptable carrier and The buffer agent mixing that the most required preservative maybe may need.Ophthalmic preparation, ear drop and eye drop are also covered by the present invention In the range of.It addition, present invention encompasses the purposes of transdermal patch agent, the another advantage that described transdermal patch agent has is for making Obtain compound and be delivered to health controllably.This type of dosage form can by by compound dissolution in or be scattered in suitable medium Prepare.Absorption enhancer can also be used for the flux increasing compound through skin.Speed can be by providing rate controlling membranes or logical Cross to be scattered in polymeric matrix or gel compound and control.

The pharmaceutically acceptable compositions that the present invention provides also can be used by nasal aerosol or inhalant.This type of Compositions according in pharmaceutical formulating art it is well known that technology prepare and saline solution can be made into, its use benzylalcohol or its His suitable preservative, absorption enhancer (in order to improve bioavailability), fluorocarbons and/or the solubilizing agent of other routine Or dispersant.

The pharmaceutically acceptable compositions that the present invention provides can be configured to oral administration.This preparation can be with food or not Use together with food.In some embodiments, the pharmaceutically acceptable compositions of the present invention is not used together with food. In other embodiments, the pharmaceutically acceptable compositions of the present invention is used together with food.

The amount of the compositions that the compound provided can be combined to produce single dosage form with carrier material will be according to being treated Patient and concrete method of application and change.The compound provided can be formulated such that can be to the trouble accepting these compositionss Person use inhibitor be 0.01-100mg/kg body weight/day dosage.

Concrete dosage and therapeutic scheme for any specific patient will depend on many factors, including the age, body weight, one As health status, sex, diet, time of application, excretion rate, drug regimen, the judgement for the treatment of physician and treated specific The order of severity of disease.Compound of formula I or the amount of its salt provided in compositions also will depend upon which the specialization in compositions Compound.

In one embodiment, the scope of the therapeutically effective amount of the compound of the present invention of every dose of parenteral administration will be About 0.01-100mg/kg, alternatively about 0.1mg/kg to 20mg/kg every day weight in patients, the initial model of typical case of compound used therefor Enclose for 0.3mg/kg/ days to 15mg/kg/ days.In another embodiment, oral unit dosage form such as tablet and capsule contains about 5mg is to the compound of the about 100mg present invention.

The example of tablet peroral dosage form comprises about 2mg, 5mg, 25mg, 50mg, 100mg, 250mg or 500mg formula (I) chemical combination Thing or its salt, and also comprise the Lactis Anhydrous of about 95-30mg, the croscarmellose sodium of about 5-40mg, about 5-30mg Polyvinylpyrrolidone (PVP) K30 and the magnesium stearate of about 1-10mg.The method preparing described tablet includes powdered Composition mixes and mixes with PVP solution further.Obtained compositions can be dried, granulate and magnesium stearate Mix and use conventional equipment to be compressed into tablet form.The example of aerosol formulation can be by by about 2-500mg compound of formula I Or its salt is dissolved in suitable buffer solution such as phosphate buffer and adds tension regulator such as salt when needed (such as chlorine Change sodium) prepare.Can such as use 0.2 micron filter filtering solution to remove the removal of impurity and pollutant.

Compound and the purposes of pharmaceutically acceptable compositions

Compound as herein described and compositions are commonly available to suppress one or more to participate in the enzyme of epigenetic regulation Activity.

Epigenetics is the losing of gene expression that research is caused by the change of various mechanism rather than potential dna sequence The change of disease.The molecular mechanism played a role in epigenetic regulation includes DNA methylation and chromatin/histone modification.Especially It is histone methylated in many epigenetic phenomenons for vital.

Chromatin (core DNA and the organized assembling of histone proteins) is the tune that multiple important nuclear process includes transcribing Joint, duplication, DNA-injury repairing and the basis of cell cycle progression.Identify many factor such as chromatin modification enzymes to exist Maintain in chromatinic dynamic equilibrium and play a significant role (Margueron etc. (2005) Curr.Opin.Genet.Dev.15: 163-176)。

Histone is chromatinic major protein components.They serve as DNA circle around bobbin, and they gene adjust Control plays a role.A total of six class histones (H1, H2A, H2B, H3, H4 and H5) are organized into two superclass: core histones (H2A, H2B, H3 and H4) and linker histone (H1 and H5).Chromatinic elementary cell is nucleosome, and described nucleosome is by ring About 147 DNA base being wound on around histone octamer to composition, described histone octamer by each core histones H2A, Two copies composition (Luger etc. (1997) Nature 389:251-260) of H2B, H3 and H4.

The aminoterminal residue of histone, particularly histone H 3 and H4 and histone H2A, H2B and H1 amino and carbonyl The residue of base end is vulnerable to the impact of various post translational modification, and described post translational modification includes: acetylation, methylate, phosphoric acid Change, ribosylation, SUMOization, ubiquitination, citrullinated, remove imido grpup and biotinylation.The core of histone H2A and H3 Also can be modified.Histone modification repairs by various biological process such as gene regulation, DNA and chromatin condensation is indispensable 's.

The protein modified i.e. demethylation of a kind of type group is by istone lysine demethylase (HKDM) or histone essence ammonia Acid demethylase catalysis.It is apparent that the family containing Jumonji domain of 2-oxoglutaric acid dependent form oxygenase represents participation The one major type of histone demethylase of genetic regulation.Although it have been found that JMJD6 is histone arginine demethylation Enzyme, but the protein containing Jumonji domain of the most nearly all description is all istone lysine piptonychia Base enzyme.The important JMJD2 that the protein containing Jumonji domain is JMJC type lysine demethylase of one class (contains Jumonji domain 2) subtribe.

GASC1 (also referred to as JMJD2C) is the 2-oxoglutaric acid dependent form istone lysine piptonychia in JMJD2 subtribe Base enzyme.GASC1 makes the tri-methylated lysine 9 on histone H 3 and lysine 36 demethylation (that is, H3K9me3 and H3K36me3) (Whetstine etc. (2006) Cell 125:467-481).Tri-methylated and heterochromatic on the lysine 9 of histone H 3 Form relevant with Transcription inhibition (Cloos etc. (2006) Nature 442:307-311).It is known that GASC1 Yu H3K4me3 and H4K20me3 combines (Huang etc. (2006) Science312:748-751).

In some embodiments, the enzyme suppressed by compound as herein described and compositions and method described herein The enzyme that it is useful is included 2-oxoglutaric acid dependent form enzyme or its isoform or mutant.In some embodiments, 2-ketone penta Diacid dependent form enzyme is the protein containing Jumonji domain.In certain embodiments, containing Jumonji domain Protein is JMJD2 subtribe member.In certain embodiments, JMJD2 subtribe member is GASC1.

The compound provided as 2-oxoglutaric acid dependent form enzyme (such as, containing the protein of Jumonji domain, Such as JMJD2, such as GASC1) or its isoform or mutant inhibitor activity can in vitro, internal or in cell line Measure.

Vitro assay includes the algoscopy measuring the inhibitory action of GASC1 or its mutant.In some embodiments, Inhibitor is combined and can be measured by the experiment of being at war with property, wherein by new inhibitor with and known radioligand be combined GASC1 is hatched together.For measure as GASC1 or the compound of the offer of the inhibitor of its mutant detailed conditions with Lower embodiment illustrates.

In some embodiments, the detection of GASC1 activity is surveyed by external istone lysine demethylase (HKDM) The method of determining realizes, and it can be to measure directly in conjunction with (on-catalytic) or enzyme process (catalysis).Class for the substrate of this type of algoscopy Type comprises the steps that (described residue carrys out the histone sequence of self-contained target lysine residue for short synthetic peptide corresponding to many residues N-end), single recombinant histones polypeptide, the histone octamer recombinated by recombinant histones and recombinant nuclear corpusculum (profit With eight aggressiveness and the specificity recombinant dna fragment of restructuring).Described recombinant nuclear corpusculum can be mononucleosome or oligoneucleosomes.Right Necessary to GASC1 function, cofactor 2-oxoglutaric acid also apply be applicable to competitive binding assay method.Mass spectral analysis and protein Marking analysis can also be used for detecting GASC1 activity；See for example the Cell125:467-481 such as Whetstine (2006).For The example of HKDM Screening test method, sees WO2007/104314 and WO 2008/089883.It should be understood that algoscopy as herein described Can be used for other HKDM protein in addition to GASC1.In certain embodiments, it is provided that compound competing with 2-oxoglutaric acid Strive.

GASC1 is relevant to proliferative disease.GASC1 gene first in esophageal squamous cell carcinoma cell line identified go out, Make its named " gene of amplification in squamous cell carcinoma 1 (GASC1) " (Yang etc. (2000) Cancer Res.60:4735- 4739).The downward that GASC1 expresses inhibits cell proliferation, and the regulation and control of histone demethylation occur relevant to tumor (Whetstine etc. (2006) Cell 125:467-481).GASC1 organizes egg with androgen receptor and another kind in vitro and in vivo Butter methylase (LSD1) interacts, and adds the expression of androgen receptor dependent form gene in prostatic cell, this Show GASC1 relevant to carcinoma of prostate (Wissmann etc. (2007) Nat.Cell Biol.9:347-353).Additionally, GASC1 base Because expanding in substrate sample breast tumor and lung carcinoma sarcomatodes, and (Han etc. (2008) Genes of transposition in MALT lymphoma Chromosomes Cancer 47:490-499；Helias etc. (2008) Cancer Genet.Cytogenet.180:51-55； Italiano etc. (2006) Cancer Genet.Cytogenet.167:122-130；Vinatzer etc. (2008) Clin Cancer Res 14:6426-6431).GASC1 plays a significant role in cancer and other proliferative diseasees.

As used herein, term " treatment (treatment) ", " treatment (treat) " " treatment (treating) " refer to Reverse, alleviate, postpone or suppress disease or disease or the progress of one or more symptom, as described herein.One In a little embodiments, treatment can be used after one or more symptom development.In other embodiments, treatment can not have Use in the case of symptom.Such as, treatment can be applied to before paresthesia epilepsy susceptible individual (such as, according to symptom history and/or According to heredity or other predisposing factors).Treatment also can proceed, such as, in order to prevent or delay it after resolution of symptoms Recurrence.

In certain embodiments, it is provided that compound suppress one or more 2-oxoglutaric acid dependent form enzymes.At some In embodiment, it is provided that compound suppress one or more to contain the enzyme of Jumonji domain.In certain embodiments, The compound provided suppresses one or more JMJD2 protein.In certain embodiments, it is provided that compound suppression GASC1. The inhibitor that compound is 2-oxoglutaric acid dependent form enzyme (such as, GASC1) provided, and be therefore applicable to treatment a kind of or The multiple disease relevant with 2-oxoglutaric acid dependent form enzyme (such as, GASC1) activity.In certain embodiments, the present invention carries A kind of method having supplied disease for treating GASC1 mediation, described method includes the change using offer to patient in need Compound or the step of its pharmaceutically acceptable compositions.

As used herein, term " GASC1 mediation " disease or condition of illness mean the most known GASC1 or its mutant Any disease played a role or other deleterious condition.Therefore, another embodiment of the present invention relates to treatment or alleviates wherein The order of severity of one or more diseases that known GASC1 or its mutant play a role.

Can the disease of the method according to the invention treatment and condition of illness include but not limited to, cancer and other proliferative disorders. In one embodiment, compound and pharmaceutically acceptable carrier, adjuvant or the excipient treatment mankind by the present invention are suffered from Person, the consumption of the compound of the wherein said present invention is that measurably suppression 2-oxoglutaric acid dependent form enzyme (such as, contains The protein of Jumonji domain, such as JMJD2, such as GASC1) activity amount.

The another kind of important protein containing Jumonji domain is H3K4 (H3 K4) demethylase, itself and group Hair-weaving is educated, cancer relevant with stem cell biology (Roesch etc. (2010) Cell 141:283-594).This kind of H3K4 demethylation Enzyme includes the JARID subtribe (such as, JARID1A and JARID1B) of histone demethylase.

JARID1A (also referred to as KDM5A) expresses at hemopoietic system camber.JARID1B (also referred to as KDM5B, PLU- 1 and RBP2-H1) it is the member of jumonji/ARID1 (JARID1) H3 K4 demethylase family.In normal cell, JARID1B expresses on a small quantity.But, JARID1B expresses at regenerating tissues (such as testis and bone marrow) camber.In cancer, The function of JARID1B is the transcriptional as oncogene, such as, and BRCA1 (Yamane etc., (2007) in breast carcinoma Molecular Cell 25:801-812).It practice, JARID1B overexpression in breast carcinoma.Also it has been reported that, JARID1B expresses at slow circulation melanoma cell camber.Therefore, the suppression of JARID1B is thin for eliminating all melanomas The important goal (fast breeding and slow circulation) (Roesch etc. (2010) Cell 141:283-594) of born of the same parents.

In some embodiments, the enzyme suppressed by compound as herein described and compositions and method described herein The enzyme that it is useful is included 2-oxoglutaric acid dependent form enzyme or its isoform or mutant.In some embodiments, 2-ketone penta Diacid dependent form enzyme is the protein containing Jumonji domain.In certain embodiments, containing Jumonji domain Protein is JMJD2 subtribe member.In certain embodiments, JMJD2 subtribe member is GASC1.In certain embodiments, Described enzyme is JARID subtribe member.In certain embodiments, described enzyme is JARID1A, PLU-1 or JMJD2B.

The compound provided is as histone demethylase (such as, containing the protein of Jumonji domain, such as, JMJD2, JMJD2B, JARID1A, JARID1B, PLU-1 or GASC1) or the activity of inhibitor of its isoform or mutant can In vitro, internal or in cell line measure.

Vitro assay includes the algoscopy measuring the inhibitory action of enzyme or its mutant.In some embodiments, press down Preparation is combined and can be measured by the experiment of being at war with property, wherein by new inhibitor with and the enzyme that is combined of known radioligand Hatch together.For measuring the detailed conditions as enzyme or the compound of the offer of the inhibitor of its mutant in following example Middle elaboration.

In some embodiments, histone demethylase is (such as, containing the protein of Jumonji domain, such as, JMJD2, JMJD2B, JARID1A, JARID1B, PLU-1 or GASC1) activity detection by external istone lysine piptonychia Base enzyme (HKDM) algoscopy realizes, and it can be to measure directly in conjunction with (on-catalytic) or enzyme process (catalysis).For these algoscopys Substrate type include: corresponding to the short synthetic peptide of many residues, (described residue carrys out the histone of self-contained target lysine residue The N-end of sequence), single recombinant histones polypeptide, the histone octamer recombinated by recombinant histones and the core of restructuring Corpusculum (utilizes eight aggressiveness and the specificity recombinant dna fragment of restructuring).Described recombinant nuclear corpusculum can be mononucleosome or few core little Body.Cofactor 2-oxoglutaric acid necessary to GASC1 function also can be applied to competitive binding assay method.Mass spectral analysis and Western blots can also be used for detecting GASC1 activity；See for example the Cell 125:467-481 such as Whetstine (2006).For the example of HKDM Screening test method, see WO 2007/104314 and WO 2008/089883.It should be understood that herein Described algoscopy can be used for other HKDM protein in addition to GASC1.In certain embodiments, the compound provided Compete with 2-oxoglutaric acid.

In certain embodiments, the compound provided suppresses one or more 2-oxoglutaric acid dependent form enzymes.At certain In a little embodiments, the compound provided suppresses one or more to contain the enzyme of Jumonji domain.In some embodiment In, the compound provided suppresses one or more JMJD2 protein.In certain embodiments, the compound provided presses down GASC1 processed.In certain embodiments, in compound suppression JARID1A, JARID1B, PLU-1 and/or JMJD2B of being provided One or more.The compound provided be these histone demethylases inhibitor and therefore be applicable to treatment with One or more diseases that the activity of one or more in JARID1A, JARID1B, PLU-1 and/or JMJD2B is relevant.At certain In a little embodiments, the invention provides a kind of for treating JARID1A-, JARID1B-, PLU-1-and/or JMJD2B-mediation The method of disease, described method includes using provided compound or its pharmaceutically acceptable group to patient in need The step of compound.

As used herein, term " JARID1A-mediation " disease or condition of illness mean the most known JARID1A or its dash forward Any disease that variant plays a role or other deleterious condition.Therefore, another embodiment of the invention relates to treatment or subtracts The order of severity of one or more diseases that the most known light JARID1A or its mutant play a role.

As used herein, term " JARID1B-mediation " disease or condition of illness mean the most known JARID1B or its dash forward Any disease that variant plays a role or other deleterious condition.Therefore, another embodiment of the invention relates to treatment or subtracts The order of severity of one or more diseases that the most known light JARID1B or its mutant play a role.

As used herein, term " PLU-1-mediation " disease or condition of illness mean the most known PLU-1 or its mutant Any disease played a role or other deleterious condition.Therefore, another embodiment of the invention relates to treatment or alleviates it In the order of severity of one or more diseases that plays a role of known PLU-1 or its mutant.

As used herein, term " JMJD2B-mediation " disease or condition of illness mean the most known JMJD2B or its sudden change Any disease that body plays a role or other deleterious condition.Therefore, another embodiment of the invention relates to treatment or alleviates The order of severity of one or more diseases that the most known JMJD2B or its mutant play a role.

Another aspect includes the purposes of formula (I) compound or its salt for suppressing KDM5.Formula (I) compound can also be used for The removing of methyl labelling on inhibition of histone lysine residue, it includes suppressing from histone h1, H2A, H2B, H3 and H4 Removing of the single-, two-or three-methyl labelling that methylates, such as H3K4 (including such as KDM5 substrate H3K4me3), therefore changes these Histone and DNA and/or the interaction of other protein, and change some heredity subsequently or protein expression.Formula (I) is changed Compound can also be used for suppressing KDM5 and reducing drug resistant cells, thus treatment or prevention drug resistant disease, such as drug resistant cancer.? In some embodiment, described disease can use formula (I) compound to treat thus prevent from forming Drug resistance, such as, at chemistry Before the target for the treatment of is undergone mutation thus is given this chemotherapeutical resistance.

In certain embodiments, combination or the inhibitory activity of formula (I) compound can be surveyed by the experiment of being at war with property Fixed, wherein by formula (I) compound with and the KDM5 enzyme that is combined of known radioligand together with hatch.For measuring as KDM5 or The detailed conditions of formula (I) compound of its mutant inhibitor illustrates in the examples below.

In certain embodiments, the detection of KDM5 activity is realized by vitro assay, and it can be directly in conjunction with (non- Catalysis) or enzyme process (catalysis) mensuration.Substrate type for these algoscopys includes: corresponding to the short synthetic peptide of many residues The N-end of histone sequence of self-contained target lysine residue (the described residue come), single recombinant histones polypeptide, by weight The histone octamer of group histone restructuring and the nucleosome of restructuring (utilize eight aggressiveness and the specificity recombinant DNA sheet of restructuring Section).Described recombinant nuclear corpusculum can be mononucleosome or oligoneucleosomes.

On the other hand a kind of method treated in patients or prevent the disease suppressed in response to KDM5 activity is included.Described Method includes formula (I) compound or its salt to patient therapeuticallv's effective dose in need.

On the other hand formula (I) compound or its pharmaceutically acceptable salt purposes in the treatment are included.The opposing party's bread Include the purposes in the treatment of the pharmaceutical composition containing formula (I) compound or its pharmaceutically acceptable salt.

On the other hand include that formula (I) compound or its pharmaceutically acceptable salt are treating the disease relevant to KDM5 activity In purposes.On the other hand include pharmaceutical composition containing formula (I) compound or its pharmaceutically acceptable salt treatment with Purposes in the disease that KDM5 activity is relevant.

On the other hand include that formula (I) compound or its pharmaceutically acceptable salt are manufacturing for treatment and KDM5 activity phase Purposes in the medicine of the disease closed.On the other hand include containing formula (I) compound or the medicine of its pharmaceutically acceptable salt Compositions purposes in manufacturing the medicine for treating the disease relevant to KDM5 activity.

In certain embodiments, disease or condition of illness be excess proliferative disease, cancer, apoplexy, diabetes, hepatomegaly, Cardiovascular disease, multiple sclerosis, alzheimer's disease, cystic fibrosis, viral disease, autoimmune disease, Atherosclerosis, restenosis, psoriasis, rheumatoid arthritis, inflammatory bowel, asthma, allergic conditions, inflammation, god Through disease, the hormone related condition disease relevant with organ transplantation, immunodeficiency disease, destructive bone disorders, proliferative diseases Disease, the condition of illness that infectious disease is relevant to cell death, thrombin induction type platelet aggregation, hepatic disease, relate to T cell Pathologic immune condition of illness, CNS disease or the bone marrow proliferative disease of activation.

In certain embodiments, treatment can be used after one or more symptom development.In other embodiments, Treatment can be used in the case of not having symptom.Such as, treatment can be applied to before paresthesia epilepsy susceptible individual (such as, according to Symptom history and/or according to heredity or other predisposing factors).Treatment also can proceed, such as, in order in advance after resolution of symptoms Prevent or delay it to recur.

On the other hand include a kind of for treating, improve or prophylaxis of cancer, drug resistance cancer or another kind of proliferative disorders Method, described method, to the mammal of this treatment of needs, the such as mankind, uses formula (I) compound or its salt of effective dose. In certain embodiments, described disease to be treated is cancer or drug resistance cancer.

The invention still further relates to a kind of for treating, improve or prophylaxis of cancer or the method for another kind of proliferative disorders, described Method is to the mammal of this treatment of needs, and especially human administration effective dose is according to the compound of the present invention.In the present invention Some aspects in, the disease having the method for the stand-by present invention to treat can be cancer.Compound as herein described and side can be used The example of the cancer of method treatment includes but not limited to, adrenal carcinoma, acinic cell carcinoma, acoustic neuroma, acral lentiginous are black Melanoma, acrospiroma, acute eosinophilic's leukemia, Di Guglielmo syndrome, acute lymphoblastic leukemia, acute Megakaryocytic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, gland Tumor, adenomatoid odontogenic tumor, adenosquamous carcinoma, adipose tissue neoplasms, adrenocortical carcinoma, adult T cell leukemia/lymphoma, attack Property NK chronic myeloid leukemia, AIDS-associated lymphoma, alveolar rhabdomyosarcoma, alveolar soft tissue sarcoma, ameloblastic fibroma, Primary cutaneous type, undifferentiated thyroid carcinoma, androgen-dependent cancer, lymphoma angioimmunoblastic T cell, Hamartoma, angiosarcoma, astrocytoma, the shaft-like tumor of atypia monster, B cell chronic lymphocytic leukemia, B cell are drenched Bar tumor, basal cell carcinoma, cancer of bile ducts, bladder cancer, blastoma, osteocarcinoma, brenner tumor, Blang's tumor, Burkitt lymphoma, breast Adenocarcinoma, the brain cancer, cancer (carcinoma), cancer in situ, carcinosarcoma, chondroma, cementoma, marrow sarcoma, chondroma, chordoma, floss Trichilemma cancer, papilloma of choroid plexus, Renal clear cell sarcoma, craniopharyngioma, cutaneous T cell lymphoma, cervical cancer, colon are straight Intestinal cancer, Degos are sick, promote connective tissue proliferative small round cell neoplasm, diffusivity large B cell lymphoid tumor, dysontogenesis Neuroepithelioma, dysgerminoma, embryonal carcinoma, endocrinal glands vegetation, endodermal sinus tumor, enteropathy relationship type T cell lymph Tumor, esophageal carcinoma, parasitus (fetus in fetu), fibroma, fibrosarcoma, follicular lymphoma, follicular thyroid carcinoma, Paraganglioma, human primary gastrointestinal cancers, germinoma, gestational choriocarcinoma, Giant cell fibroblastoma, giant cell tumor of bone, colloid Tumor, glioblastoma multiforme, glioma, cerebral glioma, glucagonoma of pancreas, gonadoblastoma, granulosa cell tumor, both sexes Embryonal cell lipoma (gynandroblastoma), carcinoma of gallbladder, gastric cancer, hemangioblastoma, head and neck cancer, hemangiopericytoma, Haematological malignancies, hepatoblastoma, liver splenic t-cell lymphoma, hodgkin's lymphomas, non Hodgkin lymphom, leaching Lubricant nature lobular carcinoma, intestinal cancer, renal carcinoma, laryngeal carcinoma, lentigo maligna, leukemia, leydig cell tumor, liposarcoma, pulmonary carcinoma, lymph Tuberculation, lymphangiosarcoma, lymphepithelioma, lymphoma, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic Lymphocytic leukemia, hepatocarcinoma, small cell lung cancer, nonsmall-cell lung cancer, MALT lymphoma, malignant fibrohistiocytoma, Malignant Peripheral Nerve Sheath Tumours, triton tumor, lymphoma mantle cell, marginal zone B-cell lymphoma, mast cell leukemia, Mediastinum germinoma, medullary carcinoma of breast, medullary thyroid carcinoma, medulloblastoma, melanoma, meningioma, merkel's cells cancer, Mesothelioma, transitivity bladder transitional cell carcinoma, Müllerian mixed tumor, mucinous neoplasms, multiple myeloma, muscular tissue vegetation, Mycosis fungoides, myxoid liposarcoma, myxoma, myxosarcoma, nasopharyngeal carcinoma, schwannoma, neuroblastoma, nerve Fibroma, neuroma, NM, cancer eye, less dash forward astrocytoma, oligodendroglioma, oncocytoma, regard Nerve sheath meningioma, optic nerve neuroma, oral cancer, osteosarcoma, ovarian cancer, pancoast's tumor, papillary thyroid carcinoma, secondary god Through plethora, pinealoblastoma, pineocytoma, pituicytoma, pituitary adenoma, pituitary tumor, plasmocytoma, polyembryony Tumor, precursor T lymphocytic lympboma, primary central nervous system lymphoma, lymphoma primary effusion, Primary peritoneal Cancer, carcinoma of prostate, cancer of pancreas, pharyngeal cancer, pseudomyxoma peritonei, renal cell carcinoma, renal medullary carcinoma, retinoblastoma, striped muscle Tumor, rhabdomyosarcoma, Richter conversion, rectal cancer, sarcoma, peripheral glioma sick (Schwannomatosis), spermocytoma, plug Er Tuoli glucagonoma, sex cords-gonadal stromal tumor, signet-ring cell carcinoma, skin carcinoma, little Lan circle glucagonoma, small cell carcinoma, soft tissue meat Tumor, somatostatinoma, flue dust wart, tumor of spine, splenic marginal zone lymphoma, squamous cell carcinoma, synovial sarcoma, plug bundle Richter scale disease, Carcinoma of small intestine, gastric cancer, t cell lymphoma, carcinoma of testis, theca cell tumor, thyroid carcinoma, transitional cell carcinoma, laryngocarcinoma, urachus Cancer, apparatus urogenitalis cancer, bladder transitional cell carcinoma, uveal melanoma, uterus carcinoma, verrucous carcinoma, pathways for vision glioma, carcinoma vulvae, Cancer of vagina, macroglobulinemia Waldenstron, papillary cystadenoma lymphomatosum (Warthin ' s tumor) and Wilms' tumor (Wilms’tumor)。

In some embodiments, the invention provides a kind of method for treating benign proliferative disease.By basis The example of the benign proliferative disease of the compounds for treating of the present invention includes but not limited to, optimum soft tissue neoplasms, bone tumor, brain With tumor of spinal cord, eyelid and orbital tumor, granuloma, lipoma, meningioma, multiple endocrine neoplasm, nasal polyp, hypophysis Tumor, prolactinoma, pseudotumor cerebri, seborrheic keratosis, polyp of stomach, thyroid nodule, cystic Tumor of Pancreas, hemangioma, vocal cords Brief summary, polyp and cyst, Castleman Tibetan sick, chronic hair disease, dermatofibroma, pilar cyst, purulent granuloma and children Year property Jeghers syndrome.

Another embodiment includes that one is applicable to internal regulation protein first in above-mentioned disease, particularly cancer Base, gene expression, cell proliferation, cell differentiation and/or the Therapeutic Method of apoptosis, it includes the patient to this treatment of needs Use and there is pharmacologically active and one or more formulas (I) compound for therapeutically effective amount.

Another embodiment includes a kind of for regulating endogenous or allos by making cell contact with formula (I) compound The method of promoter activity.

Another embodiment includes the purposes of formula (I) compound or its salt for producing pharmaceutical composition, described medicine Compositions is applied to treatment and/or prevention and/or improves disease as herein described, disease, slight illness and/or condition of illness.

Another embodiment includes the purposes for the compound of formula I or its salt producing pharmaceutical composition, described medicine Compositions is applied to treatment and/or histone demethylase is suppressed response or the disease of sensitivity and/or disease, especially by prevention It is those described above disease, such as cancer.

Present invention also offers a kind of for treatment suffer from the experimenter of one of above-mentioned condition of illness, slight illness, disease or disease such as The method of the mankind.Described method include the experimenter's administering therapeutic effective dose to this treatment of needs one or more according to this The compound of invention, it is by suppressing one or more 2-oxoglutaric acid dependent form enzymes (such as, containing Jumonji domain Protein, such as, JMJD2, such as, GASC1) and generally induce various cell to imitate by regulating protein demethylation Should, particularly induction or inhibition of gene expression, blocks cellular propagation, Cell differentiation inducing activity and/or inducing cell apoptosis plays Effect.

The present invention also provide for one be applicable to internal regulation protein methylation in above-mentioned disease, particularly cancer, Gene expression, cell proliferation, cell differentiation and/or apoptotic Therapeutic Method, it is tested that it includes to this treatment of needs Person uses has pharmacologically active and for one or more of therapeutically effective amount according to the compound of the present invention.

Present invention also offers a kind of for by make cell contact with according to the compound of the present invention to regulate endogenous or The method of allogeneic promoter activity.

The invention still further relates to provided compound and/or prevent and/or improve to carry herein in treatment for production application And the purposes of pharmaceutical composition of disease, disease, slight illness and/or condition of illness.

The invention still further relates to provided compound and/or prevent inhibition of histone piptonychia in treatment for production application The pharmaceutical composition of the response of base enzyme or the disease of sensitivity or disease (particularly those already mentioned above disease is such as cancer) Purposes.

The compound provided or compositions can use and be effective in treatment or alleviate cancer or other proliferative disorders are serious Any amount and the route of administration of degree are used.Required precise volume by the kind according to experimenter, age and general status, The seriousness infected, concrete medicament, its method of application etc. and change between experimenter and experimenter.The compound of the present invention is excellent Choosing is formulated into be easy to use and the unit dosage forms of dose uniformity.Express " unit dosage forms " as used herein to refer to be suitable for institute The most discrete medicine unit for the treatment of patient.However, it should be understood that the compound of the present invention and total every consumption per day of compositions To be determined in scope of sound medical judgment by attending doctor.Will to the most concrete patient or biological particularly effective dosage level Depend on that various factors, described factor include the seriousness of treated disease and disease；The work of the particular compound used Property；The concrete compositions used；The age of patient, body weight, general health, sex and diet；The materialization used The time of application of compound, route of administration and discharge rate；The treatment persistent period；With the particular compound combination used or simultaneously Similar factor known in the medicine used and medical domain.

The pharmaceutically acceptable compositions of the present invention can in oral administration, rectum, parenteral, brain pond, intravaginal, peritoneum In, locally (such as powder, ointment or drop), be applied to the mankind and other animals through buccal or as mouth or nasal spray etc., This depends on being treated the order of severity infected.In certain embodiments, the compound of the present invention can every day about 0.01mg/ Kg experimenter's body weight is to about 50mg/kg experimenter's body weight, and in certain embodiments, with about 1mg/kg experimenter's body weight extremely About the dosage level oral or parenteral administration of 25mg/kg experimenter's body weight, is carried out one or more times a day, thus controlling needed for obtaining Therapeutic effect.

According to an embodiment, the present invention relates to a kind of one or more suppressed in biological sample histone demethylation Enzyme is (such as, containing the protein of Jumonji domain, such as, JMJD2, JMJD2B, JARID1A, JARID1B, PLU-1, example Such as, GASC1) method of activity, it includes described biological sample and the compound of offer or the combination containing described compound The step of thing contact.

According to another embodiment, the present invention relates to a kind of histone demethylase suppressed in biological sample (such as, Containing the protein of Jumonji domain, such as, JMJD2, JMJD2B, JARID1A, JARID1B, PLU-1, such as, GASC1) Or the method for its mutant activity, it includes described biological sample and the compound of offer or the combination containing described compound The step of thing contact.

As used herein, term " biological sample " includes but not limited to, cell culture or its extract；Available from suckling The biopsy material of animal or its extract；And blood, saliva, urine, feces, seminal fluid, tear or other body fluid or its extract Thing.

In biological sample histone demethylase (such as, containing the protein of Jumonji domain, such as, JMJD2, JMJD2B, JARID1A, JARID1B, PLU-1, such as, GASC1) or the suppression of activity of its mutant be applicable to this area skill Various purposes known to art personnel.The example of these purposes includes but not limited to, blood transfusion, organ transplantation, biological specimen storage and Bioassay.

According to another embodiment, the present invention relates to histone demethylase in a kind of suppression patient and (such as, contain The protein of Jumonji domain, such as, JMJD2, JMJD2B, JARID1A, JARID1B, PLU-1, such as, GASC1) or its The method of the activity of mutant, it includes using the compound of offer or the compositions containing described compound to described patient Step.In certain embodiments, the present invention relates to one for treating by histone demethylase in patient in need (such as, containing the protein of Jumonji domain, such as, JMJD2, JMJD2B, JARID1A, JARID1B, PLU-1, such as, GASC1) or the method for its mutant mediated disease, it includes using the compound according to the present invention or its medicine to described patient The step of compositions acceptable on.These diseases describe in detail in this article.

According to the concrete condition of illness treated or disease, the other therapeutic agents generally using to treat this condition of illness also is present in A part in the compositions of the present invention or as dosage is administered alone.As used herein, generally use to treat tool The other therapeutic agents of body disease or condition of illness is considered " being suitable to treated disease or condition of illness ".

In some embodiments, described other therapeutic agents is epigenetic medicine.As used herein, term is " apparent Genetic medicine " refer to the therapeutic agent of targeting epigenetic regulator.The example of epigenetic regulator includes the group having been described above Albumen demethylase (such as, containing the protein of Jumonji domain, such as, JMJD2, JMJD2B, JARID1A, JARID1B, PLU-1, such as GASC1) and other histone demethylase, histone-lysine methyltransferase, histones Arginine methyltransferase, histone deacetylase, histone acetyltransferases, histone methylase and DNA methyl Transferring enzyme.Histone deacetylase includes but not limited to, Vorinostat (vorinostat).

Compound is co-administered with other medicaments

Formula (I) compound or its salt can be used alone or use for the pharmaceutical agent combinations for the treatment of with other.Such as, described medicine Second medicament of thing combination preparation or dosage can have complementary activity so that they do not produce to formula (I) compound Adverse effect.Described compound can be used together in single medicine compositions or be administered alone.In one embodiment, change Compound or pharmaceutically acceptable salt can be co-administered with cytotoxic agent with treatment proliferative disease and cancer.

Term " co-administered " refers to use or continuous administration formula (I) compound or its salt the most individually simultaneously With one or more other active pharmaceutical ingredients (including cytotoxic agent and radiotherapy).If not using simultaneously, then institute State compound to use in the similar time being closely adjacent to each other.Additionally, whether compound is used unimportant with same dosage form, example As, a kind of compound can local application and another kind of compound is orally available uses.

Those other medicaments separately can be executed with the compositions containing the compounds of this invention as a part for multiple dose scheme With.Alternatively, those medicaments can be the single dosage form mixed with the compound of the present invention in single compositions A part.If the part as multiple dose scheme is used, then the two activating agent can simultaneously, successively or be spaced one The section time, generally it is spaced five hours and submits.

As used herein, term " combines ", " combination " and relevant term refer to simultaneously or sequentially use basis The therapeutic agent of the present invention.Such as, the compound of the present invention can be with another kind of therapeutic agent simultaneously or sequentially with single unit dosage form Or use with single unit dosage form together.Therefore, the invention provides a kind of contained I, other therapeutic agents and medicine The single unit dosage form of acceptable carrier, adjuvant or excipient on.

The compounds of this invention and the other therapeutic agents of single dosage form can be combined to produce with carrier material and (comprising as above institute Those compositionss of the other therapeutic agents stated) the two amount will change according to the host treated and specific method of application. In certain embodiments, the compositions of the present invention is configured to so that can application dosage be 0.01-100mg/kg body weight/day The compounds of this invention.

Typically, can co-administered have for the disease treated or any medicament of the activity of condition of illness.This kind of medicament Example can be at the Cancer Principles and Practice of of V.T.Devita and S.Hellman (editor) Oncology, sixth version (February 15 calendar year 2001), finds in Lippincott Williams&Wilkins Publishers. Those of ordinary skill in the art can characteristic based on involved medicine and the disease combination that distinguishes which kind of medicament be useful.

In one embodiment, Therapeutic Method includes co-administered formula (I) compound or its pharmaceutically acceptable salt With at least one cytotoxic agent.As used herein, term " cytotoxic agent " refer to suppression or stop cell function and/or Cause the material of cell death or destruction.Cytotoxic agent includes but not limited to, radiosiotope (such as, At²¹¹、I¹³¹、 I¹²⁵、Y⁹⁰、Re¹⁸⁶、Re¹⁸⁸、Sm¹⁵³、Bi²¹²、P³²、Pb²¹²Radiosiotope with Lu)；Chemotherapeutant；Growth inhibitor； Enzyme and fragment thereof such as nucleolytic enzyme；And the small molecule toxins of toxin such as antibacterial, fungus, plant or animal origin or enzymatic activity poison Element, including its fragment and/or variant.

Exemplary cells toxic agents is selected from: anti-micro-pipe agent, platinum coordination complex, alkylating agent, antibiotic agent, topoisomerase Enzyme II inhibitor, antimetabolite, topoisomerase I inhibitor, hormone and hormone analogs, signal transduction pathway inhibitor, non- Receptor tyrosine kinase angiogenesis inhibitor, immunotherapeutic agent, rush apoptosis agent, the inhibitor of LDH-A；Fatty acid biological Synthetic inhibitor；Cell cycle signals inhibitor；HDMC inhibitor, proteasome inhibitor；And cancer metabolic poison.

" chemotherapeutant " includes the chemical compound being applicable to treat cancer.The example of chemotherapeutant includes that angstrom sieve replaces Buddhist nun (Genentech/OSI Pharm.), bortezomib (Millennium Pharm), disulfiram, Epigallocatechin Gallate, Salinosporamides A (salinosporamide A), Ka Feizuo Rice (carfilzomib), 17-AAG (geldanamycin), radicicol, lactic acid dehydrogenase (LDH-A), fulvestrant (AstraZeneca), Sutent (Pfizer/Sugen), letrozole (Novartis), imatinib mesylate (Novartis)、finasunate(Novartis), oxaliplatin (Sanofi), 5-FU (5-fluorouracil), first Acyl tetrahydrofolic acid, rapamycin (sirolimus,Wyeth), Lapatinib ( GSK572016, Glaxo Smith Kline), Luo Nafani (SCH 66336), Sorafenib (Bayer Labs), gefitinib (AstraZeneca), AG1478, alkylating agent such as thiotepa andRing Phosphamide；Alkyl sulfonic ester, such as busulfan, an improsulfan and piposulfan；Aziridine, such as benzo DOPA, carboquone, U.S. Appropriate DOPA (meturedopa) and frequent micturition bar (uredopa)；Aziridine and methylmelamine, including altretamine, triethylene Melamine, triethylenephosphoramide, triethylene thiophosphoramide and front three melamine；Acetyl genin (particularly bullatacin and Bullatacin ketone)；Camptothecine (includes hycamtin and irinotecan)；Bryostatin；Sponge statin (callystatin)；CC- 1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues)；Beads algin (particularly beads algin 1 He Beads algin 8)；Adrenocortical hormone (includes prednisone and prednisolone)；CPA；5 alpha-reductases (include non- That male amine and dutasteride)；Vorinostat, romidepsin, LBH589, valproic acid, Moses department he (mocetinostat) are many Plast statin；Aldesleukin, Talcum times carcinomycin (including synthetic analogues, KW-2189 and CB1-TM1)；Eleutherobin.； Water ghost any of several broadleaf plants alkali；Crawl a Corallium Japonicum Kishinouye alcohol (sarcodictyin)；Spongistatin；Chlormethine (nitrogen mustard), as chlorambucil, Chlornaphazine, chlorine phosphamide, estramustine, ifosfamide, chlormethine (mechlorethamine), nitrobine hydrochloride, American and French Logical sequence, novembichin, phenesterin, prednimustine, trofosfamide, uracil mustard；Nitroso ureas, such as carmustine, chlorine Urea rhzomorph, fotemustine, lomustine, nimustine and Ranimustine；Antibiotic, such as enediyne antibiotic (such as, Jia Liche Mycin, especially calicheamicin γ 1I and calicheamicin ω 1I (Angew Chem.Intl.Ed.Engl.199433:183- 186)；Reach endomycin, including reaching endomycin A；Diphosphate, such as clodronate；Ai Sipeila mycin；And neocarzinostain NCS is raw Color group and related color albumen enediyne antibiotic chromophore), aklavine, D actinomycin D, antramycin, azaserine, Bleomycin, actinomycin C (cactinomycin), carubicin, carminomycin, carzinophillin, chromomycin, dactinomycin, Daunorubicin, detorubicin, 6-diazo-5-oxn-l-norieucin,(doxorubicin), morpholine Generation-doxorubicin, Cyanomorpholino-doxorubicin, 2-pyrrolin also-doxorubicin and deoxygenate doxorubicin), epirubicin, Esorubicin, idarubicin, marcellomycin, mitomycin such as ametycin, mycophenolic acid, nogalamycin, Olivomycin, training Lip river mycin, porfiromycin, puromycin, triferricdoxorubicin, rodorubicin, streptonigrin, streptozocin, tubercidin, crow benzene Beautiful department, zinostatin, a left side is soft compares star；Antimetabolite, such as methotrexate and 5-fluorouracil (5-FU)；Folacin, such as two First folic acid, methotrexate, Pteropterin, trimetrexate；Purine analogue, such as fludarabine, Ismipur, ITG, sulfur Guanine；Pyrimidine analogue, such as ancitabine, azacitidine, 6-azauridine, carmofur, cytosine arabinoside, double uracil deoxyriboside, goes Oxygen floxuridine, enocitabine, floxuridine；Androgen, in calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testis Ester；Antiadrenergic drug, as smooth in aminoglutethimide, mitotane, Qu Luosi；Folic acid supplement, such as formyl tetrahydrofolic acid；Vinegar Portugal aldehyde Lactone；Aldophosphamide glucosides；Amino-laevulic acid；Eniluracil；Amsacrine；Atrimustine (bisantrene)；Bisantrene；Depend on Reach Qu Sha；Defosfamide；Demecolcine；Diaziquone；Eflornithine；Elliptinium acetate；Epsilon；Etoglucid；Ganite (Fujisawa).； Hydroxyurea；Lentinan；Lonidamine；Maytansinol, such as maytansine and ansamitocin；Mitoguazone；Mitoxantrone；Piperazine does not reaches Alcohol；C-283；Pentostatin；Benzene carrys out beautiful spy；Pirarubicin；Losoxantrone；Podophyllinic acid；2-ethyl hydrazides；Procarbazine；Polysaccharides compound (JHS Natural Products, Eugene, OR)；Razoxane；Rhizomycin；Sizofiran；Spirogermanium； Tenuazonic acid；Triaziquone；2,2', 2 "-RA3；Trichothecene (particularly T-2 toxin, verrucarine A, Roridine A and Diacetoxysciroenol)；Urethane；Vindesine；Dacarbazine；Mannomustine；Mitobronitol；Dibromo is defended Lance alcohol；Pipobroman；Jia Xituo star (gacytosine)；Cytosine arabinoside (" Ara-C ")；Cyclophosphamide；Thiotepa；Taxane, Such as TAXOL (paclitaxel；Bristol-Myers Squibb Oncology, Princeton, N.J.),The albumin through engineering approaches nanoparticle formulations (American of (without castor oil hydrogenated), paclitaxel Pharmaceutical Partners, Schaumberg, Ill.) and(docetaxel, docetaxel； Sanofi-Aventis)；Chlorambucil；(gemcitabine)；6-thioguanine；Mercaptopurine；First ammonia butterfly Purine；Platinum analogs, such as cisplatin and carboplatin；Vinblastine；Etoposide (VP-16)；Ifosfamide；Mitoxantrone；Vincristine；(vinorelbine)；Mitoxantrone；Teniposide；Edatrexate；Daunomycin；Aminopterin；Ka Peita ShoreIbandronate；CPT-11；Topoisomerase enzyme inhibitor RFS 2000；α-difluorometylornithine (DMFO)；Retinoid, such as tretinoin；And above-mentioned arbitrary pharmaceutically acceptable salt, acid and derivant.

Chemotherapeutant also includes: (i) plays regulation or the suppression antihormone agent to the hormonal action of tumor, as anti-female sharp Element and selective estrogen receptor modulators (SERM), (include including such as tamoxifenCitric acid he Moses is fragrant), raloxifene, droloxifene, idoxifene (iodoxyfene), 4-hydroxytamoxifen, trioxifene, Lei Luoxi Sweet smell, LY117018, onapristone and(citric acid Toremitene)；(ii) suppression regulates female sharp in adrenal gland The aromatase inhibitor of aromatase that element produces, such as 4 (5)-imidazoles, aminoglutethimide,(tumer ground is pregnant Ketone),(exemestane；Pfizer), formestane, fadrozole,(vorozole),(letrozole；Novartis) and(Anastrozole；AstraZeneca)；(iii) anti-hero swashs Element, such as flutamide, nilutamide, bicalutamide, leuprorelin and goserelin；Buserelin, triptorelin, tumer hydroxyl are pregnant Ketone, diethylstilbestrol, premarin, fluoxymesterone, all trans retinoic acids, fenretinide and troxacitabine (1,3-dioxolanes Nucleoside analogue of cytosine)；(iv) kinases inhibitor；(v) lipid kinase inhibitors；(vi) antisense oligonucleotide, especially Those antisense oligonucleotides of suppression gene expression in the signal transduction path involving abnormal cell proliferation, such as PKC-α, Raf and H-Ras；(vii) ribozyme such as vegf expression inhibitor is (such as,) and HER2 expression Inhibitor；(viii) vaccine, such as gene therapeutic vaccine, such as,With rIL-2；Topoisomerase 1 inhibitor, as rmRH；And (ix) above-mentioned arbitrary pharmaceutically acceptable salt, acid and derivant.

Chemotherapeutant also includes antibody, as Ah coming organize monoclonal antibody (Campath), Avastin ( Genentech)；Cetuximab (Imclone)；Victibix (Amgen), profit Appropriate former times monoclonal antibody (Genentech/Biogen Idec), handkerchief trastuzumab (2C4, Genentech), Herceptin (Genentech), tositumomab (Bexxar, Corixia) with And antibody drug conjugate Ji trastuzumab Austria azoles rice star (Wyeth).As having treatment potentiality Medicament includes with other Humanized monoclonal antibodies of the compound combination of the present invention: Ah pool's pearl monoclonal antibody, A Sai pearl monoclonal antibody, A Li Pearl monoclonal antibody (atlizumab), Ba Pin pearl monoclonal antibody, Avastin, not bank trastuzumab, cedelizumab, match trastuzumab, Cidfusituzumab, cidtuzumab, daclizumab, according to storehouse pearl monoclonal antibody, efalizumab, epratuzumab, strategic point profit pearl Monoclonal antibody, felvizumab, virtue trastuzumab, lucky trastuzumab, azoles rice star difficult to understand, English trastuzumab difficult to understand, her monoclonal antibody, draw Bei Zhudan Anti-, lintuzumab, horse trastuzumab, mepolizumab, not dimension pearl monoclonal antibody, motovizumab, natalizumab, the appropriate pearl of Buddhist nun Monoclonal antibody, nolovizumab, numavizumab, auspicious pearl monoclonal antibody difficult to understand, omalizumab, palivizumab, handkerchief examine pearl monoclonal antibody, Pecfusituzumab, pectuzumab, training gram pearl monoclonal antibody, Lucentis, Ruili pearl monoclonal antibody (reslivizumab), Rayleigh pearl Monoclonal antibody, resyvizumab, rovelizumab, ruplizumab, sibrotuzumab, cedelizumab, rope soil pearl monoclonal antibody, for his pearl Monoclonal antibody, he spend pearl monoclonal antibody, he profit pearl monoclonal antibody, special non-pearl monoclonal antibody, torr pearl monoclonal antibody (tocilizumab), toralizumab, Tucotuzumab celmoleukin, tucusituzumab, umavizumab, crow pearl monoclonal antibody, excellent spy gram monoclonal antibody, to tie up western pearl single Resist and anti-IL-8-12 (ABT-874/J695, Wyeth Research and Abbott Laboratories), described Anti-IL-8-12 is to identify that the human sequence's exclusively recombinated of IL-12p40 protein is complete by genetic modification Long IgG₁λ antibody.

Chemotherapeutant also includes " EGFR inhibitor, ", and it refers to be combined with EGFR or otherwise direct and EGFR phase Interaction also prevents or reduces the compound of its signaling activity, and be alternatively referred to as " EGFR antagonist ".This medicament Example include the antibody that is combined with EGFR and little molecule.The example of the antibody being combined with EGFR includes MAb 579 (ATCC CRL HB 8506)、MAb 455(ATCC CRL HB8507)、MAb 225(ATCC CRL 8508)、MAb 528(ATCC CRL 8509) (see, U.S. Patent number 4,943,533, Mendelsohn etc.) and variant, such as chimeric antibody 225 (C225 or C etuximab；) and the human antibodies 225 (H225) reinvented (see, WO 96/40210, Imclone Systems Inc.)；Human epidermal growth factor receptor targeting antibodies IMC-11F8 (Imclone) completely；Be combined with EGFR II type mutant is anti- Body (U.S. Patent number 5,212,290)；The humanization inosculating antibody being combined with EGFR as described in U.S. Patent number 5,891,996 Body；And the humanized antibody being combined with EGFR, as ABX-EGF or Victibix (see WO98/50433, Abgenix/ Amgen)；EMD 55900 (the Eur.J.Cancer 32A:636-640 (1996) such as Stragliotto)；For EGFR's and use In humanization EGFR antibody EMD7200 (horse trastuzumab) of EGF and the TGF-α competition that EGFR combines, (EMD/Merck)；People EGFR antibody HuMax-EGFR (GenMab)；It is referred to as E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 and E7.6.3 And the fully human antibodies described in the US 6,235,883；MDX-447(Medarex Inc)；And mAb 806 or humanization MAb 806 (Johns etc., J.Biol.Chem.279 (29): 30375-30384 (2004)).Described anti-EGFR can be with cell toxicant Property agent is puted together, and therefore produces immunoconjugates (see, e.g., EP659,439A2, Merck Patent GmbH).EGFR antagonism Agent includes little molecule, such as at U.S. Patent number: 5,616,582,5,457,105,5,475,001,5,654,307,5,679, 683、6,084,095、6,265,410、6,455,534、6,521,620、6,596,726、6,713,484、5,770,599、6, 140,332、5,866,572、6,399,602、6,344,459、6,602,863、6,391,874、6,344,455、5,760, 041,6,002,008 and 5,747,498 and following PCT publication: WO98/14451, WO98/50038, WO99/09016 and Compound described in WO99/24037.Concrete little molecule EGFR antagonist includes that (CP-358774, angstrom sieve replaces OSI-774 Buddhist nun,Genentech/OSI Pharmaceuticals)；PD 183805 (CI 1033,2-acrylamide, N- [4-[(3-chloro-4-fluorophenyl) amino]-7-[3-(4-morpholinyl) propoxyl group]-6-quinazolyl]-, dihydrochloride, PfizerInc.)；ZD1839, gefitinib4-(3 '-chloro-4 '-fluoroanilino)-7-methoxyl group-6-(3- Quinoline is for propoxyl group) quinazoline, AstraZeneca)；ZM 105180 ((6-amino-4-(3-aminomethyl phenyl-amino)-quinazoline, Zeneca)；(N8-(3-chloro-4-fluoro-phenyl)-N2-(1-methyl-pi-4-base)-pyrimido [5,4-d] is phonetic for BIBX-1382 Pyridine-2,8-diamidogen, Boehringer Ingelheim)；PKI-166 ((R)-4-[4-[(1-phenylethyl) amino]-1H-pyrroles And [2,3-d] pyrimidine-6-base]-phenol)；(R)-6-(4-hydroxy phenyl)-4-[(1-phenylethyl) amino]-7H-pyrrolo- [2,3-d] pyrimidine)；CL-387785 (N-[4-[(3-bromophenyl) amino]-6-quinazolyl]-2-butyne amide)；EKB-569 (N-[4-[(3-chloro-4-fluorophenyl) amino]-3-cyano group-7-ethyoxyl-6-quinolyl]-4-(dimethylamino)-2-butylene acyl Amine) (Wyeth)；AG1478(Pfizer)；AG1571(SU 5271；Pfizer)；Double EGFR/HER2 tyrosine kinase inhibitors, As Lapatinib (GSK572016 or N-[the chloro-4-of 3-[(3-fluorophenyl) methoxyl group] phenyl]-6 [5 [[[2 first Base sulfonyl) ethyl] amino] methyl]-2-furyl]-4-quinazoline amine).

Chemotherapeutant also includes " tyrosine kinase inhibitor, " comprising: the EGFR target that is previously mentioned in earlier paragraphs To medicine；Little molecule HER2 tyrosine kinase inhibitor, such as the TAK165 purchased from Takeda；ErbB2 receptor tyrosine kinase Oral selective depressant CP-724,714 (Pfizer and OSI)；Double-HER inhibitor, such as EKB-569 (purchased from Wyeth), its Preferably in combination with EGFR but simultaneously suppress HER2 and EGFR overexpression cell；Lapatinib (GSK572016；Purchased from Glaxo- SmithKline), it is oral HER2 and EGF R tyrosine kinase inhibitor；PKI-166 (purchased from Novartis)；General-HER Inhibitor, such as Canertinib (CI-1033；Pharmacia)；Raf-1 inhibitor, as purchased from ISIS Pharmac euticals Antisense agent ISIS-5132, its suppression Raf-1 signal conduction；The TK inhibitor of non-HER targeting, as imatinib mesylate (Purchased from Glaxo SmithK line)；Many targeting tyrosine kinase inhibitor, as Sutent (Purchased from Pfizer)；Vegf receptor tyrosine kinase inhibitor, as Vata draw Buddhist nun (PTK787/ZK222584, Purchased from Novartis/Schering AG)；MAPK extracellular regulated kinases I inhibitor CI-1040 (purchased from Pharmacia)；Quinoline Oxazoline, such as PD153035,4-(3-chloroanilino) quinazoline；Pyridopyrimidine class；Pyrimido-pyrimidine；Pyrrolopyrimidine, Such as CGP 59326, CGP 60261 and CGP 62706；Pyrazolopyrimidines type, 4-(phenyl amino)-7H-pyrroles [2,3-d] is phonetic Pyridine；Curcumin (two Resina Ferulae sulfonyl methane, 4,5-double (4-fluorobenzene amido) phthalimides)；Containing nitrothiophene moieties Cheese Fu Siting；PD-0183805(Warner-Lamber)；Antisense molecule (such as, with HER coding nucleic acid be combined those Antisense molecule)；Quinoxaline (U.S. Patent number 5,804,396)；Tryphostins (U.S. Patent number 5,804,396)；ZD6474 (Astra Zeneca)；PTK-787(Novartis/Schering AG)；General-HER inhibitor, such as CI-1033 (Pfizer)； Affinitac(ISIS 3521；Isis/Lilly)；Imatinib mesylate PKI 166 (Novartis)；GW2016(Glaxo SmithKline)；CI-1033(Pfizer)；EKB-569(Wyeth)；Semaxinib (Pfizer)；ZD6474(AstraZeneca)；PTK-787(Novartis/Schering AG)；INC-1C11 (Imclone), Rapamycin (sirolimus,)；Or as described in any following patent disclosure: U.S. Patent number 5, 804,396；WO 1999/09016(American Cyanamid)；WO 1998/43960(American Cyanamid)；WO 1997/38983(Warner Lambert)；WO 1999/06378(Warner Lambert)；WO 1999/06396(Warner Lambert)；WO 1996/30347(Pfizer,Inc)；WO 1996/33978(Zeneca)；WO 1996/3397(Zeneca) And WO 1996/33980 (Zeneca).

Chemotherapeutant also includes: dexamethasone, interferon, Colchicine, metoprine, cyclosporin, amphotericin, Metronidazole, Ah coming organize monoclonal antibody, A Li retinoic acid, allopurinol, amifostine, arsenic trioxide, asparaginase, the BCG that lives, Bevacizumab, bexarotene, cladribine, clofarabine, Aranesp, denileukin, dexrazoxane, A Fayi moor Spit of fland, erlotinib, Fei Gesi stop, Supprelin (Roberts)., ibritumomab tiuxetan, Intederon Alpha-2a, Interferon Alpha-2b, lenalidomide, Levamisole, mesna, methoxsalen, nandrolone, nelarabine 506u, nofetumomab, oprelvekin, Pa Lifuming, pamidronic acid Salt, pegademase (pegademase), pegaspargase, training filgrastim, pemetrexed disodium, plicamycin, porfimer sodium, quina Crin, rasburicase, Sargramostim, temozolomide, VM-26,6-TG, toremifene, retinoic acid, ATRA, valrubicin, azoles come Phosphonate and zoledronic acid and pharmaceutically acceptable salt thereof.

Chemotherapeutant also includes: hydrocortisone, hydrocortisone acetate, cortisone acetate, neopentanoic acid tixocortol, Triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinonide, times his rice Pine, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, hydrocortisone-17-butyrate, hydrogenation can Pine-17-valerate, Ah can's sieve betamethasone dipropionate, celestone-V, betamethasone dipropionate, prednicarbate, chlorine Times Ta Song-17-butyrate, clobetasol-17-propionic ester, fluocortolone alkyl caproate, fluocortolone pivalate and fluocortolone acetic acid Ester；Immunoselection antiinflammatory peptide (ImSAID) such as Phe-Gln-glycine (FEG) and D-isomeric forms thereof (feG)(IMULAN BioTherapeutics,LLC)；Antirheumatic such as azathioprine, ciclosporin (cyclosporin A), D-penicillium sp Amine, gold salt, hydroxychloroquine, leflunomide minocycline (leflunomideminocycline), sulfasalazine, neoplasm necrosis Factor-alpha (TNF α) blocker such as Embrel (Enbrel), infliximab (Remicade), adalimumab (Humira), match trastuzumab (Cimzia), dagger-axe profit wood monoclonal antibody (Simponi), interleukin 1 (IL-1) blocker such as Ah that White stagnant element (Kineret), T cell stimulate blocker such as Orencia (Orencia), interleukin-6 (IL-6) blocker altogether As held in the palm pearl monoclonal antibodyInterleukin-13 (IL-13) blocker Tathagata gold bead monoclonal antibody (lebrikizumab)；Interferon-ALPHA (IFN) blocker such as Raleigh pearl monoclonal antibody (Rontalizumab)；β 7 integrin blocker Such as rhuMAb β 7；IgE channel blocker the most anti-M1 element；The heterotrimer LTa1/ β that secretion homotrimer LTa3 and film combine 2 blocker such as anti-lymphotoyin α (LTa)；Radiosiotope (such as, At²¹¹、I¹³¹、I¹²⁵、Y⁹⁰、Re¹⁸⁶、Re¹⁸⁸、Sm¹⁵³、 Bi²¹²、P³²、Pb²¹²And the radiosiotope of Lu)；Miscellany research reagent such as sulfur platinum (thioplatin), PS-341, fourth Acid phenenyl ester, ET-18-OCH₃Or farnesyl transferase inhibitor (L-739749, L-744832)；Polyhydric phenols such as Quercetin, white Herba chenopodii Reed alcohol, piceatannol, epigallocatechin gallate (EGCG), theaflavin, flavonol, procyanidin, belulinic acid Betulinic acid and derivative Thing；Autophagy inhibitor such as chloroquine；Delta-9-Tetrahydrocannabinol (dronabinol,)；Beta-lapachone；Lapachol；Autumn Tazettine；Belulinic acid Betulinic acid；Acetyl group camptothecine, scopoletin and 9-aminocamptothecin)；Podophyllotoxin；FtorafurBexaroteneDiphosphate such as clodronate is (such as,Or), etidronic acidNE-58095, zoledronic acid/azoles carry out phosphine HydrochlorateAlendronic Acid saltPamldronateTiludronic acid SaltOr profit plug phosphateAnd EGF-R ELISA (EGF-R)；Vaccine is such asVaccine；Piperazine Li Fuxin, cox 2 inhibitor (such as, celecoxib or Ai Tuokaoxi), albuminous body suppress Agent (such as, PS341)；CCI-779；Tipifarnib (R11577)；Sorafenib, ABT510；Bcl-2 inhibitor such as Ao Limosen SodiumChina fir fine jade；Farnesyl transferase inhibitor such as Luo Nafani (SCH 6636, SARASAR^TM)； And above-mentioned arbitrary pharmaceutically acceptable salt, acid or derivant；And above two or more kinds of combinations, such as CHOP, It is the abbreviation of combination treatment of cyclophosphamide, amycin, vincristine and prednisolone；And FOLFOX, it is by Ao Shali Platinum (ELOXATIN^TM) with 5-FU and the abbreviation of therapeutic scheme of formyl tetrahydrofolic acid combination.

Therapeutic agent also includes having analgesia, the antipyretic and NSAID (non-steroidal anti-inflammatory drug) of antiinflammatory action.NSAID includes cyclo-oxygenase Non-selective inhibitor.The instantiation of NSAID includes that aspirin, propanoic derivatives are (such as ibuprofen, fenoprofen, ketone Lip river Sweet smell, flurbiprofen, oxaprozin and naproxen), acetogenin (as fragrant in indomethacin, sulindac, etodolac, double chlorine Acid), enolic acid derivative (such as piroxicam, meloxicam, tenoxicam, a former times health, lornoxicam and isoxicam), fenamic acid Derivant (such as mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid) and cox 2 inhibitor are (such as celecoxib, Chinese mugwort Torr examines former times, lumiracoxib, Parecoxib, rofecoxib, rofecoxib and valdecoxib).NSAID may indicate that in symptom Alleviate condition of illness, such as rheumatoid arthritis, osteoarthritis, inflammatory arthropathy, ankylosing spondylitis, psoriatic arthritis, Lai Teer Cotard, acute gout, dysmenorrhea, Bone Pains from Metastesis, headache and migraine, postoperative pain, drawn by inflammation and tissue injury That rises is slight to moderate pain, heating, intestinal obstruction and renal colic.

In certain embodiments, chemotherapeutant includes but not limited to, amycin, dexamethasone, vincristine, ring phosphorus Amide, fluorouracil, hycamtin, interferon, platinum derivatives, taxanes (such as, paclitaxel, docetaxel), Herba Catharanthi Rosei Alkaloid (such as, vincaleucoblastine), anthracycline (such as, amycin), epipodophyllotoxin (such as, etoposide), cisplatin, MTOR inhibitors (such as, rapamycin), methotrexate, actinomycin D, dolastatin 10, colchicine, trimetrexate, Metoprine, cyclosporin, daunorubicin, teniposide, amphotericin, alkylating agent (such as, chlorambucil), 5-fluorine urine is phonetic Pyridine, camptothecine, cisplatin, metronidazole and imatinib mesylate etc..In other embodiments, the compound of the present invention and life Thing medicament such as Avastin or Victibix combined administration.

In certain embodiments, the compound of the present invention or its pharmaceutically acceptable compositions with selected from following arbitrarily The antiproliferative of one or more or chemotherapeutic combination are used: 1: PN: WO02056903 PAGE: 25 claimed protein, aldesleukin, Ah coming organize monoclonal antibody, A Li Retinoic acid, allopurinol, altretamine, amifostine, Anastrozole, arsenic trioxide, asparaginase, azacitidine, Live BCG, bevacizumab, fluorouracil, bexarotene, bleomycin, bortezomib, busulfan, calusterone, capecitabine, Camptothecine, carboplatin, carmustine, Cetuximab, chlorambucil, cladribine, clofarabine, cyclophosphamide, arabinose born of the same parents Glycosides, dactinomycin, Aranesp, daunorubicin, denileukin, dexrazoxane, docetaxel, doxorubicin (in Property), doxorubicin hydrochloride, dromostanolone propionate, epirubicin, Epoetin Alfa, Erlotinib, estramustine, etoposide phosphate pool Glycosides, etoposide, exemestane, filgrastim, floxuridine, fludarabine, fulvestrant, gefitinib, gemcitabine, Ji are appropriate Pearl monoclonal antibody, goserelin acetate, Supprelin (Roberts)., hydroxyurea, ibritumomab tiuxetan, idarubicin, ifosfamide, methanesulfonic acid Imatinib, Intederon Alpha-2a, Interferon Alpha-2b, irinotecan, lenalidomide, letrozole, formyl tetrahydrofolic acid, acetic acid bright third Rayleigh, levamisole, lomustine, megestrol acetate, melphalan, purinethol, 6-MP, mesna, methotrexate, methoxy Sarin, ametycin, mitotane, mitoxantrone, nandrolone, nelarabine 506u, nofetumomab, oprelvekin, oxaliplatin, purple China fir alcohol, Pa Lifuming, pamldronate, pegademase, pegaspargase, training filgrastim, pemetrexed disodium, pentostatin, piperazine Pool bromine alkane, plicamycin, porfimer sodium, procarbazine, quinacrine, rasburicase, Rituximab, Sargramostim, Suo La Non-Buddhist nun, streptozocin, maleic acid Sutent, Talcum, tamoxifen, temozolomide, teniposide, VM-26, testolactone, sulfur bird Purine, 6-TG, phosphinothioylidynetrisaziridine, topotecan, toremifene, tositumomab, Herceptin, retinoic acid, ATRA, uracil nitrogen Mustard, valrubicin, vinblastine, vincristine, vinorelbine, zoledronate or zoledronic acid.

Can include but not limited to the example of other medicaments that the inhibitor of the present invention combines: for Alzheimer Therapeutic agent, example hydrochloric acid donepezil and rivastigmine bright；For parkinsonian therapeutic agent, as L-DOPA/ carbidopa, Entacapone, Ropinrole, pramipexole, bromocriptine, pergolide, artane and amantadine；Multiple for treating The medicament of sclerosis (MS), such as interferon-β (such as,With), Glatiramer acetate and mitoxantrone；For The therapeutic agent of asthma, such as albuterol and Menglusitena；For treating schizoid medicament, such as Zyprexa, Risperidal, Seroquel and haloperidol；Anti-inflammatory agents, as corticosteroid, tnf blockers, IL-1RA, azathioprine, cyclophosphamide and Sulfasalazine；Immunomodulator and immunosuppressant, as cyclosporin, tacrolimus, rapamycin, Mycophenolate Mofetil, Interferon, corticosteroid, cyclophosphamide, azathioprine and sulfasalazine；Neurotrophic factor, such as acetylcholinesterase Inhibitor, MAO inhibitor, interferon, anticonvulsant, ion channel blocking agents, riluzole and anti-Parkinson agent；For treating the heart The medicament of angiopathy, such as beta-Blocking agent, ACE inhibitor, diuretic, nitrate esters, calcium channel blocker and Statins；For The medicament for the treatment of hepatic disease, such as corticosteroid, cholestyramine, interferon and antiviral agent；For treating the medicine of blood disorder Agent, such as corticosteroid, leukemia agent and somatomedin；And for treating the medicament of immunodeficiency disease, such as third kind of ball Albumen.

In certain embodiments, the compound of the present invention or its pharmaceutically acceptable salt and monoclonal antibody or SiRNA therapeutic combination is used.

Additionally, chemotherapeutant includes pharmaceutically acceptable salt, the acid of any chemotherapeutant as herein described or spreads out Biological and two of which or more kinds of combinations.

In those compositionss comprising other therapeutic agents, the compound of this other therapeutic agents and the present invention can work in coordination with work With.Needed for therefore, in these compositionss, the amount of other therapeutic agents will be less than in merely with the monotherapy of this therapeutic agent Amount.In certain embodiments, can be with application dosage for 0.01 1 in these compositionss, between 000 μ g/kg body weight/day Other therapeutic agents.

The amount of the other therapeutic agents being present in the compositions of the present invention will less than generally using comprise this therapeutic agent as The amount that the compositions of sole active is used.In certain embodiments, the other therapeutic agents in presently disclosed compositions Amount in the range of be typically found in comprise this medicament as the amount in the compositions of sole therapy activating agent about 50% to 100%.

On the other hand use formula (I) compound or the treatment of its pharmaceutically acceptable salt or the drug resistance of prevention patient are included Property.Such as, the method for the drug resistant cancer of a kind for the treatment of or prevention patient includes or and cytotoxic agent independent to described patient Formula (I) compound of combined administration therapeutically effective amount.In certain embodiments, described individuality is selected as passing through cytotoxicity Agent (such as, targeted therapy, chemotherapy and/or radiotherapy) is treated.In certain embodiments, described individuality with Starting treatment before cytotoxic agents, described treatment includes formula of using (I) compound or its pharmaceutically acceptable salt.? In some embodiment, described individuality accepts to include formula (I) compound or its pharmaceutically acceptable salt and cell toxicant simultaneously The treatment of property agent.In certain embodiments, formula (I) compound or its pharmaceutically acceptable salt add cancer sensitive time Between and/or delay the drug-fast generation of cancer.

Especially, the method that there is provided herein the individual cancer for the treatment of, it includes using (a) formula (I) compound to individuality Or its pharmaceutically acceptable salt and (b) cytotoxic agent (such as, targeted therapy, chemotherapy and/or radiotherapy).At certain In a little embodiments, formula (I) compound or its pharmaceutically acceptable salt and the respective amount of cytotoxic agent are effective in increase cancer Time that disease is sensitive and/or delay cancerous cell that cancer therapeutic agent is produced resistance.In certain embodiments, formula (I) compound Or its pharmaceutically acceptable salt and the respective amount of cytotoxic agent are effective in and increase the treatment of cancer comprising cancer therapeutic agent Effect.Such as, in certain embodiments, there is no (lacking) formula (I) compound or it is pharmaceutically acceptable with including using The treatment of the cancer therapeutic agent of the effective dose of salt (such as, standard care type is treated) is compared, formula (I) compound or its pharmaceutically may be used The salt and the respective amount of cytotoxic agent that accept can increase effect effectively.In certain embodiments, do not have with including using Treatment (such as, the standard care of the cytotoxic agent of the effective dose of (lacking) formula (I) compound or its pharmaceutically acceptable salt Type is treated) to compare, formula (I) compound or its pharmaceutically acceptable salt and the respective amount of cytotoxic agent can increase sound effectively Answer (such as, totally linearization).

The method that increase effect of including the treatment of cancer of cytotoxic agent in individuality is also provided herein, it include to Described individuality uses the cytotoxicity of formula (I) compound of (a) effective dose or its pharmaceutically acceptable salt and (b) effective dose Agent.

The method that there is provided herein the individual cancer for the treatment of, wherein treatment of cancer includes using (a) effective dose to individuality Formula (I) compound or its pharmaceutically acceptable salt and the cytotoxic agent of (b) effective dose, wherein do not have (to lack with including using Treatment (such as, the standard care type of the cytotoxic agent of the effective dose of formula (I) compound or its pharmaceutically acceptable salt less) Treatment) to compare, described treatment of cancer has effect of increase.

Delay in individuality and/or method that cancer therapeutic agent is developed immunity to drugs by prophylaxis of cancer additionally, there is provided herein, It includes using the thin of formula (I) compound of (a) effective dose or its pharmaceutically acceptable salt and (b) effective dose to described individuality Cellular toxicity agent.

There is provided herein treatment and suffer from the individual method of cancer, described individuality has the producing cancer therapeutic agent of increase Drug-fast probability, described method includes using formula (I) compound of (a) effective dose to described individuality or it pharmaceutically can connect The salt being subject to and the cytotoxic agent of (b) effective dose.

The method that in the individuality of suffer from cancer increase sensitivity to cancer therapeutic agent is also provided herein, it include to Described individuality uses the cytotoxicity of formula (I) compound of (a) effective dose or its pharmaceutically acceptable salt and (b) effective dose Agent.

The method that the time that extends cancer therapeutic agent sensitivity is also provided herein in the individuality suffer from cancer, it includes The cytotoxicity of formula (I) compound of (a) effective dose or its pharmaceutically acceptable salt and (b) effective dose is used to described individuality Agent.

There is provided herein the method extending the persistent period to cytotoxic agent response in the individuality suffer from cancer, its bag Include the cell toxicant using formula (I) compound of (a) effective dose or its pharmaceutically acceptable salt and (b) effective dose to described individuality Property agent.

There is provided herein a kind of formula for therapeutic treatment (I) compound or its pharmaceutically acceptable salt.

There is provided herein a kind of formula for preventing and treating property or therapeutic treatment proliferative disorders (I) compound or its pharmaceutically Acceptable salt.

There is provided herein a kind of for suppress 2-oxoglutaric acid dependent form enzyme or its mutant activity formula (I) compound or Its pharmaceutically acceptable salt.

There is provided herein a kind of disease formula (I) compound for treating GASC1 mediation or its pharmaceutically acceptable salt.

There is provided herein a kind of for suppressing formula (I) compound of JARID family enzymatic activity or its pharmaceutically acceptable Salt.

There is provided herein a kind of formula (I) compound for treating the disease that JARID mediates or it is pharmaceutically acceptable Salt.

There is provided herein a kind of formula (I) compound of effect for increasing the treatment of cancer containing cytotoxic agent or its Pharmaceutically acceptable salt.

There is provided herein a kind of pharmaceutically acceptable for treating individual formula (I) compound suffering from cancer or its Salt, described individuality has the probability developing immunity to drugs cytotoxic agent of increase.

There is provided herein a kind of formula (I) compound for treating cancer or its pharmaceutically acceptable salt.

There is provided herein a kind of formula (I) compound for increasing treatment of cancer effect or its pharmaceutically acceptable salt.

There is provided herein a kind of formula (I) chemical combination for delaying and/or prevent cancer from cytotoxic agent being developed immunity to drugs Thing or its pharmaceutically acceptable salt.

There is provided herein a kind of formula (I) compound for increasing the sensitivity to cytotoxic agent or it pharmaceutically can connect The salt being subject to.

There is provided herein formula (I) compound of a kind of time for extending cancer therapeutic agent sensitivity or it pharmaceutically may be used The salt accepted.

There is provided herein formula (I) compound or its pharmacy of a kind of persistent period for extending the response to treatment of cancer Upper acceptable salt.

There is provided herein formula (I) compound or its pharmaceutically acceptable salt to be applicable to suppress 2-oxoglutaric acid to depend in preparation Rely the purposes in the active medicine of type enzyme or its mutant.

There is provided herein formula (I) compound or its pharmaceutically acceptable salt to be applicable to treat GASC1 mediation in preparation Purposes in the medicine of disease.

There is provided herein formula (I) compound or its pharmaceutically acceptable salt to be applicable to suppress JARID family enzyme in preparation Purposes in the medicine of activity.

There is provided herein formula (I) compound or its pharmaceutically acceptable salt to be applicable to treat JARID mediation in preparation Purposes in the medicine of disease.

There is provided herein formula (I) compound or its pharmaceutically acceptable salt to be applicable to increase containing cytotoxicity in preparation Purposes in the medicine of effect of the treatment of cancer of agent.

There is provided herein formula (I) compound or its pharmaceutically acceptable salt preparation be applicable to treat suffer from cancer Purposes in the medicine of body, described individuality has the probability developing immunity to drugs cytotoxic agent of increase.

There is provided herein formula (I) compound or its pharmaceutically acceptable salt preparing be applicable to the medicine for the treatment of cancer Purposes.

There is provided herein formula (I) compound or its pharmaceutically acceptable salt to be applicable to increase treatment of cancer effect in preparation Medicine in purposes.

There is provided herein formula (I) compound or its pharmaceutically acceptable salt to be applicable to delay and/or prevent cancer in preparation Purposes in the medicine that cytotoxic agent is developed immunity to drugs by disease.

There is provided herein formula (I) compound or its pharmaceutically acceptable salt preparation be applicable to increase cytotoxic agent quick Purposes in the medicine of perception.

There is provided herein formula (I) compound or its pharmaceutically acceptable salt preparation be applicable to extend cancer therapeutic agent quick Purposes in the medicine of perception time.

There is provided herein formula (I) compound or its pharmaceutically acceptable salt to be applicable to extend treatment of cancer sound in preparation Purposes in the medicine of the persistent period answered.

In some embodiment of any means, described cytotoxic agent is targeted therapy.In certain embodiments, Described targeted therapy is one or more in EGFR antagonist, RAF inhibitor and/or PI3K inhibitor.

In some embodiment of any means, described targeted therapy is EGFR antagonist.In some of any means In embodiment, described EGFR antagonist is N-(3-ethynyl phenyl)-6, double (2-the methoxy ethoxy)-4-quinazoline amine of 7- And/or its pharmaceutically acceptable salt.In certain embodiments, described EGFR antagonist is N-(3-ethynyl phenyl)-6, Double (2-the methoxy ethoxy)-4-quinazoline amine of 7-.In certain embodiments, described EGFR antagonist is N-(4-(3-fluorine benzyl Epoxide)-3-chlorphenyl)-6-(5-((2-(methyl sulphonyl) ethylamino) methyl) furan-2-base) quinazoline-4-amine, two 4- Toluene sulfonic acide ester or its pharmaceutically acceptable salt (such as, Lapatinib).

In some embodiment of any means, described targeted therapy is RAF inhibitor.In certain embodiments, Described RAF inhibitor is BRAF inhibitor.In certain embodiments, described RAF inhibitor is CRAF inhibitor.Real at some Executing in scheme, described BRAF inhibitor is Wei Luofeini.In certain embodiments, described RAF inhibitor is 3-(2-cyano group Acrylate-2-yl)-N-(4-methyl-3-(3-methyl-4-oxo-3,4-dihydroquinazoline-6-base amino) phenyl) Benzoylamide or its Pharmaceutically acceptable salt (such as, AZ628 (CAS#878739-06-1)).

In some embodiment of any means, described targeted therapy is PI3K inhibitor.

In some embodiment of any means, described cytotoxic agent is chemotherapy.In some of any means In embodiment, described chemotherapy is taxanes.In certain embodiments, described taxanes is paclitaxel.At certain In a little embodiments, described taxanes is docetaxel.

In some embodiment of any means, described cytotoxic agent is platinum class medicament.In certain embodiments, Described platinum class medicament is carboplatin.In certain embodiments, described platinum class medicament is cisplatin.Some embodiment party in any means In case, described cytotoxic agent is taxanes and platinum class medicament.In certain embodiments, described taxanes is Ramulus et folium taxi cuspidatae Alcohol.In certain embodiments, described taxanes is docetaxel.In certain embodiments, described platinum class medicament is card Platinum.In certain embodiments, described platinum class medicament is cisplatin.

In some embodiment of any means, described cytotoxic agent is vinca alkaloids.Some embodiment party In case, described vinca alkaloids is vinorelbine.In some embodiment of any means, described chemotherapy is nucleoside Analog.In certain embodiments, described nucleoside analog is gemcitabine.

In some embodiment of any means, described cytotoxic agent is radiotherapy.

In some embodiment of any means, formula (I) compound or its pharmaceutically acceptable salt and described cell Toxic agents (such as, targeted therapy, chemotherapy and/or radiotherapy) is used simultaneously.In certain embodiments, formula (I) is changed Compound or its pharmaceutically acceptable salt can (such as, targeted therapy, chemotherapy and/or radiation be controlled at described cytotoxic agent Treat) before and/or use simultaneously.

In some embodiment of any means, described cancer be pulmonary carcinoma, breast carcinoma, cancer of pancreas, colorectal carcinoma and/ Or melanoma.In certain embodiments, described cancer is pulmonary carcinoma.In certain embodiments, described pulmonary carcinoma is NSCLC. In certain embodiments, described cancer is breast carcinoma.In certain embodiments, described cancer is melanoma.

The compound of the present invention or its pharmaceutical composition can be incorporated in the compositions of coating implantable medical device, Described medical treatment device such as prosthese, artificial valve, blood vessel graft, support and conduit.Such as, intravascular stent has been used for overcoming the narrowest Narrow (restenosis of vessel wall after injury).But, use the patient of support or other implantable devices to have clot and formed and blood The danger of platelet activation.Can be by with comprising histone demethylase (such as, containing the protein of Jumonji domain, example Such as, JMJD2, JMJD2B, JARID1A, JARID1B, PLU-1, such as, GASC1) the pharmaceutically acceptable compositions of inhibitor Device described in precoating, thus prevent or alleviate these harmful effects.Implantable device with the compound coating of the present invention For another embodiment of the invention.

Illustration

As following example are described, in some exemplary, according to following general process preparationization Compound.Should be understood that although conventional method describes the synthesis of some compound of the present invention, but following conventional method and ability Additive method known to the those of ordinary skill of territory can be applicable to all compounds and each these compound as herein described Subclass and kind.

The general synthetic method illustrated in scheme 1-4 separates with the general LCMS confirming as LCMS method A-LCMS method F Program is for preparing the compound of embodiment 1-432 as described in detail below.

General synthetic method

Scheme 1 (method A)

The general synthesis of compound 6 and compound 7 is shown in scheme 1.Using the NaOEt EtOH as the backflow of alkali In make the condensation of 5-amino-1H-pyrazoles-4-formonitrile HCN (1) and alkyl malonate thus obtain intermediate 3.Subsequently with phosphorous oxychloride React thus generate two chloromethylated intermediates 4, use sodium hydroxide optionally to hydrolyze to obtain common chloromethylated intermediate 5.Then with There is Suzuki cross-coupling reaction thus obtain compound 6 in boric acid or borate, can be used halogenide R³X further N-alkane Base is to obtain compound 7.

Scheme 2 (method B)

Replacement synthesis (method B) of compound 6 is shown in scheme 2.Make 5-amino-1H-pyrazoles-4-formonitrile HCN (1) and ketone Ester 8 is condensed in the presence of acetic acid or titanium tetrachloride thus obtains compound 6.

Scheme 3 (method C)

Replacement synthesis (method C) of compound 6 is shown in scheme 3.Chemical combination is processed with the N-halogen succinamide in DMF Thing 9 is to obtain halogenide 10.Occur Suzuki cross-coupling reaction also can obtain compound 6 with boric acid or borate subsequently.

Scheme 4 (method D)

Under Pd catalytic condition, chloride 5 also can with amine coupling thus obtain compound 11.Chloride in compound 5 Bromide 12 can be further converted in the presence of TMSBr.Then bromide 12 and ethanol generation coupling reaction obtain compound 13。

General LCMS program

LCMS method A (Agilent 10-80AB, ELSD, 2 minute)

Reality is carried out having on Agilent 6110MSD mass spectrometric Agilent 1200HPLC (with PDA detector) Test, use ESI as ionization source, use Xtimate C18,3um, 30 × 2.1mm and 1.2mL/min flow velocity.Solvent orange 2 A is for containing The water of 0.038%TFA, and solvent B is the acetonitrile containing 0.02%TFA.Gradient is run: start with 10%A and 90%B, Run to 20%A and 80%B in 0.9 minute, then keep 0.6 minute under 20%A and 80%B.Total run time is 2 points Clock.

LCMS method B (Agilent 0-30AB, ELSD, 2 minute)

Reality is carried out having on Agilent 6110MSD mass spectrometric Agilent 1200HPLC (containing PDA detector) Test, use ESI as ionization source, use Xtimate C18,3um, 30 × 2.1mm and 1.2mL/min flow velocity.Solvent orange 2 A is for containing The water of 0.038%TFA, and solvent B is the acetonitrile containing 0.02%TFA.Gradient is run: start with 100%A and 90%B, Run to 30%A and 70%B in 0.9 minute, then keep 0.6 minute under 30%A and 70%B.Total run time is 2 points Clock.

LCMS method C (Agilent 0-60AB, ELSD, 2 minute)

Reality is carried out having on Agilent 6110MSD mass spectrometric Agilent 1200HPLC (containing PDA detector) Test, use ESI as ionization source, use Xtimate C18,3um, 30 × 2.1mm and 1.2mL/min flow velocity.Solvent orange 2 A is for containing The water of 0.038%TFA, and solvent B is the acetonitrile containing 0.02%TFA.Gradient is run: start with 100%A, at 0.9 minute Interior operation, to 40%A and 60%B, then keeps 0.6 minute under 40%A and 60%B.Total run time is 2 minutes.

LCMS method D (Agilent 30-90AB, ELSD, 2 minute)

Reality is carried out having on Agilent 6110MSD mass spectrometric Agilent 1200HPLC (containing PDA detector) Test, use ESI as ionization source, use Xtimate C18,3um, 30 × 2.1mm and 1.2mL/min flow velocity.Solvent orange 2 A is for containing The water of 0.038%TFA, and solvent B is the acetonitrile containing 0.02%TFA.Gradient is run: start with 30%A and 70%B Run to 10%A and 90%B in 0.9 minute, then keep 0.6 minute under 10%A and 90%B.Total run time is 2 points Clock.

LCMS method E (SHIMADZU, 5-95AB, ELSD, 1.5 minute)

Having, SHIMADZU 2010EV MSD mass spectrometric SHIMADZU 20A HPLC (containing PDA detector) is enterprising Row experiment, uses ESI as ionization source, uses Merk RP-18e 2x 25mm post and 1.5mL/min flow velocity.Solvent orange 2 A is for containing The water of 0.038%TFA, and solvent B is the acetonitrile containing 0.02%TFA.Gradient run: start with 95%A and 5%B, with After 0.7 minute in run to 5%A and 95%B.By this solvent than maintaining 0.4 minute, extensive in 0.4 minute subsequently afterwards Arrive 95%A and 5%B again.Total run time is 1.5 minutes.

LCMS method F (Agilent 5-95AB, ELSD, 10 minute)

At the Agilent being connected with HPLC Agilent 1200 system with the UV detector monitored at 254nm Test in 6140 quadrupole LC/MS systems, and mass spectrograph ionizes Mode scans 90-1300amu with ESI+.This system uses Agilent SB C18 (1.8um30x 2.1mm) post, maintains at 25 DEG C and flow velocity is 0.4mL/min.Solvent orange 2 A is for containing The water of 0.05%TFA, and solvent B is the acetonitrile containing 0.05%TFA.Gradient is run: with 95% in initial 0.3 minute A and 5%B starts, in operations in 6.5 minutes subsequently to 5%A and 95%B.By this solvent than maintaining 1.5 minutes, afterwards subsequently 0.1 minute in return to 95%A and 5%B.Total run time is 10 minutes.

Embodiment

Embodiment 1 (method A)

Step 1

6-isopropyl-5,7-dioxo-4,5,6,7-tetrahydro-pyrazole also [1,5-a] pyrimidine-3-formonitrile HCN

Sodium (9.0g, 391mmol) is slowly added in EtOH (400mL), and at 26 DEG C, described mixture is stirred 1.5 hours until sodium consumes completely.In gained NaOEt solution add 5-amino-1H-pyrazoles-4-formonitrile HCN (20g, 185mmol), 2-diethyl isopropyl (37.5g, 185mmol) it is subsequently added into.Reactant mixture is refluxed 16 hours. Subsequently reactant mixture is cooled to room temperature and dilutes with MTBE (200mL).Precipitate is collected by filtration and uses water dissolution.Will Described solution is acidified to pH 2-3 with dense HCL, thus obtains pale precipitation thing, is filtered and drying under reduced pressure is required to obtain The white solid product (30g, 74% productivity) wanted.¹H NMR(400MHz,DMSO-d₆) δ 8.23 (s, 1H), 3.23 (q, J= 6.8Hz, 1H), 1.20 (d, J=6.8Hz, 6H).

Step 2

5,7-bis-chloro-6-isopropylpyrazol also [1,5-a] pyrimidine-3-formonitrile HCN

By 6-isopropyl-5,7-dioxo-4,5,6,7-tetrahydro-pyrazoles also [1,5-a] pyrimidine-3-formonitrile HCN (30g, 137mmol) join POCl in five batches₃(100mL), in, it is subsequently added into DMA (17g, 137mmol).Will reaction Mixture is heated to 110 DEG C and stirs 16 hours.After being cooled to room temperature, decompression removes POCl₃And by residue with water (200mL) Dilution, extracts with EtOAc (200mL x 3).By the Organic substance of merging through anhydrous Na₂SO₄It is dried and concentrates.By thick residue from Recrystallization in EtOAc and hexane (1:5) thus obtain required white solid product (25g, 71% productivity).¹H NMR (400MHz,DMSO-d₆) δ 8.86 (s, 1H), 3.73-3.68 (m, 1H), 1.41 (d, J=7.2Hz, 6H).LCMS(ESI):m/z 255.1[M+H]⁺, RT=1.12 minute (LCMS method A).

Step 3

5-chloro-6-isopropyl-7-oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN

To 5, the THF (100mL) of 7-bis-chloro-6-isopropylpyrazol also [1,5-a] pyrimidine-3-formonitrile HCN (10g, 39.2mmol) Solution adds NaOH aqueous solution (100mL, 2M).When after reaction completely, mixture is stirred 16 hours at 26 DEG C.With 1M After HCl/water solution is acidified to pH=1, mixture EtOAc (500mL x 3) is extracted.By the organic layer of merging through anhydrous Na₂SO₄It is dried and is concentrated by rotary evaporator.By thick residue from EtOAc/ hexane (1:5) recrystallization thus obtain required The white solid product (6.8g, 73% productivity) wanted.¹H NMR(400MHz,DMSO-d₆)δ8.29(s,1H),3.30-3.23(m, 1H), 1.30 (d, J=7.2Hz, 6H).LCMS(ESI):m/z 237.2[M+H]⁺, RT=1.11 minute (LCMS method C).

Embodiment 2

5-chloro-6-ethyl-7-oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN

In similar program as shown in Example 1, by 5-amino-1H-pyrazoles-4-formonitrile HCN and 2-ethyl malonic acid second Diester prepares title compound with 36% productivity.¹H NMR(400MHz,MeOH-d₄) d 8.09 (s, 1H), 2.70 (q, J= 7.6Hz, 2H), 1.12 (t, J=7.6Hz, 3H)；LCMS(ESI)m/z 223.1[M+H]⁺, RT=1.02 minute (LCMS method C)。

Embodiment 3

5-(furan-3-base)-6-isopropyl-7-oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN

To 5-chloro-6-isopropyl-7-oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN (200mg, 0.845mmol), furan-3-ylboronic acid (104mg, 0.93mmol) and K₂CO₃The dioxane of (233mg, 1.69mmol): H₂O(5: 1,3mL) solution adds Pd (dppf) Cl₂(70mg, 0.085mmol).Reaction vessel is sealed and in the microwave of 110 DEG C Heat 30 minutes.After cooling to room temperature, reactant mixture concentrated and pass through the fast of the use DCM eluting containing 0-10%MeOH Speed silica gel column chromatography purification residue is to obtain crude product, then is further purified with preparation HPLC thus obtains required White solid product (40mg, 18% productivity).¹H NMR(400MHz,DMSO-d₆)δ13.26(s,1H),8.35(s,1H),8.09 (s, 1H), 7.88 (s, 1H), 6.74 (s, 1H), 2.90-2.85 (m, 1H), 1.26 (d, J=6.4Hz, 6H).LCMS(ESI):m/ z 269.1[M+H]⁺, RT=0.95 minute (LCMS method A).

Embodiment 4

5-(furan-3-base)-6-isopropyl-4-methyl-7-oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN

To containing 5-(furan-3-base)-6-isopropyl-7-oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN (320mg, 1.19mmol) and K₂CO₃In DMF (3mL) solution of (330mg, 2.39mmol) add MeI (0.12mL, 1.79mmol).After being stirred at room temperature 6 hours, by mixture at EtOAc (30mL) and H₂Distribute between O (30mL) and separate Two-layer.Water layer EtOAc (30mL) is extracted.By organic layer saline (50mL) washing merged, through anhydrous Na₂SO₄Be dried, Filter and concentrate, and by preparation HPLC purification residue thus obtain required white solid product (15mg, 4% Productivity).¹H NMR(400MHz,DMSO-d₆)δ8.47(s,1H),8.00(s,1H),7.98(s,1H),6.71(s,1H),3.60 (s, 1H), 2.65-2.60 (m, 1H), 1.22 (d, J=7.2Hz, 6H).LCMS(ESI):m/z283.1[M+H]⁺, RT=1.01 Minute (LCMS method A).

Embodiment 5

6-isopropyl-7-oxo-5-(1H-pyrazoles-4-base)-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN

In nitrogen atmosphere, to containing 5-chloro-6-ethyl-7-oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN (10g, 42.26mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan alkane-2-bases)-1H-pyrazoles (10.66mg, 54.93mmol) and Na₂CO₃The DME:H of (8.96g, 84.51mmol)₂O (2:1,150mL) solution adds Pd (dppf)Cl₂(3.1g, 4.23mmol).Reactant mixture is heated 16 hours at 110 DEG C.After cooling to room temperature, will be anti- Answer mixture to concentrate and pass through to use the flash silica gel chromatography purification residue of the DCM eluting containing 0-10%MeOH, thus Obtain required brown solid (7.0g, 62% productivity).¹H NMR(400MHz,DMSO-d₆)δ13.42(s,1H), 13.09 (s, 1H), 8.36 (s, 1H), 8.17 (s, 1H), 7.78 (s, 1H), 2.97 (m, 1H), 1.29 (d, J=7.2Hz, 6H). LCMS(ESI):m/z 269.2[M+H]⁺, RT=1.02 minute (LCMS method C).

Embodiment 6

5-(1-(Cvclopropvlmethvl)-1H-pyrazoles-4-base)-6-isopropyl-7-oxo-4,7-dihydro-pyrazolo [1,5-a] Pyrimidine-3-formonitrile HCN

To containing 6-isopropyl-7-oxo-5-(1H-pyrazoles-4-base)-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN (100mg, 0.372mmol) and (bromomethyl) cyclopropane (50mg, 0.372mmol) mixture in DMF (2mL) adds Cs₂CO₃(364mg, 1.12mmol).At room temperature reactant mixture is stirred 16 hours.Reactant mixture is filtered and by filtrate By preparation HPLC purification thus obtain required product as off-white solid (20mg, 17% productivity).¹H NMR (400MHz,CD₃OD) δ 8.20 (s, 1H), 8.12 (s, 1H), 7.76 (s, 1H), 4.11 (d, J=7.2Hz, 2H), 3.10-3.03 (m, 1H), 1.37 (d, J=7.2Hz, 6H), 1.37 (m, 1H), 0.68-0.63 (m, 2H), 0.47-0.43 (m, 2H)；LCMS (ESI)m/z269.1[M+H]⁺, RT=0.73 minute (LCMS method E).

Embodiment 7

Step 1

The bromo-1-of 4-(acrylate-1-alkene-2-base)-1H-pyrazoles

Cu (OAc) will be contained₂(6.18g, 34.02mmol) and 2, the DCE of 2'-bipyridyl (5.31g, 68.04mmol) (30mL) solution is heated to 70 DEG C, continues 15 minutes.Then this mixture is transferred to 4-bromo-1H-pyrazoles (5g, 34.02mmol), trifluoro (acrylate-1-alkene-2-base) potassium borate (10.07g, 68.04mmol) and Na₂CO₃(7.21g, 68.04mmol) DCE (20mL) suspension in.Described mixture is stirred 8 hours at 70 DEG C, then by it between EtOAc and 1N HCl Distribution.By water layer with EtOAc (20mL x 2) extraction and by the organic layer saline washing merged, through anhydrous Na₂SO₄It is dried also Concentrate thus obtain crude product, by crude product described in flash silica gel chromatography (hexane/EA=200/1) purification thus obtain Required colorless oil as product (4.0g, 66% productivity).¹H NMR(400MHz,CDCl₃)δ7.70(s,1H),7.54(s, 1H), 5.28 (d, J=4.4Hz, 1H), 4.72 (s, 1H), 2.45 (s, 3H).

Step 2

The bromo-1-of 4-(1-methylcyclopropyl groups)-1H-pyrazoles

At N₂Under atmosphere, in ice bath, DCM (10mL) solution of TFA (2.38mL, 32.08mmol) is added dropwise to Et₂In the DCM (30mL) of Zn (1M toluene solution, 32mmol).After 20 minutes, it is added dropwise over CH₂I₂(8.5g, 32.08mmol's) DCM (10mL) solution is also stirred for 20 minutes.The DCM (5mL) being subsequently adding the bromo-1-of 4-(acrylate-1-alkene-2-base)-1H-pyrazoles is molten Liquid also removes ice bath.After being stirred at room temperature 24 hours, mixture is used saturated NH₄Cl solution cancellation with DCM (20mL x 2) extraction.By the Organic substance of merging through anhydrous Na₂SO₄It is dried, filters and concentrates thus obtain crude product, by Flash silica post Crude product described in chromatography (hexane/EA=100/1) purification thus obtain required yellow oil product (490mg, 15% produce Rate).¹H NMR(400MHz,DMSO-d₆) δ 7.50 (s, 1H), 7.43 (s, 1H), 1.59 (s, 3H) 1.24 (t, J=6.0Hz, 2H), 0.91 (t, J=6.8Hz, 2H).

Step 3

1-(1-methylcyclopropyl groups)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan alkane-2-base)-1H-pyrrole Azoles

In a nitrogen atmosphere, will contain the bromo-1-of 4-(1-methylcyclopropyl groups)-1H-pyrazoles (650mg, 3.23mmol), 4,4, 4', 4', 5,5,5', 5'-prestox-2, double (1,3,2-dioxaborolan alkane) (820mg, 3.23mmol), the Pd of 2'- (PPh₃)₂Cl₂(210mg, 0.3mmol) and CH₃Dioxane (10mL) mixture of COOK (792mg, 8.07mmol) is at 100 DEG C Lower heating 5 hours.After being cooled to room temperature, mixture is evaporated and passes through the quick of the use Hex containing 0-10%EtOAc Silica gel column chromatography purification residue, thus obtain required white solid product (160mg, 20% productivity).¹H NMR (400MHz,CDCl₃):δ7.80(s,1H),7.77(s,1H),1.32(s,12H),1.27-1.23(m,2H),0.92-0.89 (m,2H)。

Step 4

6-isopropyl-5-(1-(1-methylcyclopropyl groups)-1H-pyrazoles-4-base)-7-oxo-4,7-dihydro-pyrazolo [1,5- A] pyrimidine-3-formonitrile HCN

In a nitrogen atmosphere, to containing 5-chloro-6-ethyl-7-oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN (160mg, 0.64mmol), 1-(1-methylcyclopropyl groups)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan alkane-2- Base)-1H-pyrazoles (151mg, 0.64mmol) and Na₂CO₃The DME/H of (136mg, 1.28mmol)₂In the solution of O (2/1,3mL) Add Pd (dppf) Cl₂(44mg, 0.06mmol).Under microwave condition, reactant mixture is heated 30 minutes at 110 DEG C. After being cooled to room temperature, reactant mixture concentrates and passes through to use the Flash silica post of the Hex containing 50-100%EtOAc Chromatography purification residue, thus obtain crude product, then by rpHPLC (Gemini C₁₈150x 25mm x 10um, 35- 65%MeCN/H₂O) it is further purified thus obtains required white solid product (62mg, 30% productivity).¹H NMR (400MHz,DMSO-d₆)δ13.01(s,1H),8.37(s,1H),8.23(s,1H),7.71(s,1H),2.98-2.92(m, 1H), 1.64 (s, 6H), 1.29 (d, J=7.2Hz, 6H), 1.26-1.24 (m, 2H), 1.00-0.97 (m, 2H).LCMS(ESI): m/z323.1[M+H]⁺, RT=1.18 minute (LCMS method C).

Embodiment 8

Step 1

The fluoro-1-of the bromo-5-of 4-((2-(trimethyl silyl) ethyoxyl) methyl)-1H-pyrazoles

At N₂Under, to the bromo-1-of 4-((2-(trimethyl silyl) ethyoxyl) methyl)-1H-pyrazoles at-78 DEG C THF (50mL) solution of (5.0g, 18.0mmol) is added dropwise over LDA (18.0mL, 36.0mmol, 2M are in THF).-78 After stirring 30 minutes at DEG C, reactant mixture is cooled to-100 DEG C and in reactant mixture, is added dropwise over N-fluoro-N-(phenyl Sulfonyl) benzsulfamide (11.37g, 36.0mmol are dissolved in 50mL THF), and it is little that reactant mixture stirs at-78 DEG C 1 Time.Use saturated NH₄Cl (100mL) cancellation is reacted and uses methyl tertiary butyl ether(MTBE) (100mL) to extract.By organic layer through anhydrous Na₂SO₄ It is dried, filters and concentrates thus obtain crude product, by using the flash chromatography on silica gel of the Hex containing 0-2%EtOAc Crude product described in method purification, thus obtain the required colorless oil 4-fluoro-1-of bromo-5-((2-(trimethyl silyl) ethoxy Base) methyl)-1H-pyrazoles (460mg, 9% productivity).¹H NMR(400MHz,CDCl₃) δ 7.42 (d, J=2.4Hz, 1H), 5.37 (s, 2H), 3.63 (d, J=8.4Hz, 2H), 0.93 (d, J=8.4Hz, 2H), 0.01 (s, 9H).

Step 2

The fluoro-4-of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan alkane-2-base)-1-((2-(trimethyl first silicon Alkyl) ethyoxyl) methyl)-1H-pyrazoles

To containing the 4-fluoro-1-of bromo-5-((2-trimethyl silyl) ethyoxyl) methyl at 0 DEG C)-1H-pyrazoles (460mg, THF (10mL) solution 1.56mmol) adds iPrMgBr (4.67mL, 4.67mmol, 1M are in THF), and reactant is existed Stir 1 hour under room temperature.It is subsequently adding 2-methoxyl group-4,4,5,5-tetramethyl-1,3,2-dioxaborolan alkane (985mg, 6.23mmol), and by mixture it is stirred at room temperature 2 hours.Use saturated NH₄Cl (20mL) cancellation is reacted and uses methyl tertbutyl Ether (50mL) extracts.By organic layer through anhydrous Na₂SO₄It is dried, filters and concentrates thus obtain thick object, by using containing 0- Thick object described in the flash silica gel chromatography purification of the Hex of 3%EtOAc, thus obtain required colorless oil Product (360mg, 68% productivity).¹H NMR(400MHz,CDCl₃) δ 7.63 (d, J=3.2Hz, 1H), 5.35 (s, 2H), 3.62 (d, J=8.0Hz, 2H), 1.33 (s, 12H), 0.91 (d, J=8.0Hz, 2H), 0.02 (s, 9H).

Step 3

5-(the fluoro-1-of 5-((2-(trimethyl silyl) ethyoxyl) methyl)-1H-pyrazoles-4-base)-6-isopropyl-7- Oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN

In a nitrogen atmosphere, to containing 5-chloro-6-ethyl-7-oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN (144mg, 0.61mmol), the fluoro-4-of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan alkane-2-bases)-1-((2- (trimethyl silyl) ethyoxyl) methyl)-1H-pyrazoles (260mg, 0.76mmol) and Na₂CO₃(161mg, 1.52mmol's) DME:H₂O (2:1,3mL) solution adds Pd (dppf) Cl₂(56mg, 0.076mmol).Under microwave condition, reaction is mixed Thing heats 30 minutes at 110 DEG C.After being cooled to room temperature, reactant mixture is concentrated and passes through to use the DCM containing 0-3%MeOH The flash silica gel chromatography purification residue of eluting, thus obtain required brown solid (220mg crude product). LCMS m/z 417.0[M+H]⁺。

Step 4

5-(5-fluoro-1H-pyrazoles-4-base)-6-isopropyl-7-oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-3-first Nitrile

To containing 5-(the fluoro-1-of 5-((2-(trimethyl silyl) ethyoxyl) methyl)-1H-pyrazoles-4-base)-6-isopropyl Anhydrous DCM (4mL) solution of base-7-oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN (220mg crude product) adds Enter TFA (2mL).At room temperature reactant mixture is stirred 1 hour.Reactant mixture is concentrated and residue is re-dissolved in In HCl/ dioxane (20mL).Reactant mixture is stirred at room temperature 16 hours and concentrates thus obtain can be directly used for next The crude product (150mg) of step.LCMS m/z 286.9[M+H]⁺。

Step 5

5-(3-fluoro-1-isopropyl-1H-pyrazoles-4-base)-6-isopropyl-7-oxo-4,7-dihydro-pyrazolo [1,5-a] Pyrimidine-3-formonitrile HCN

To containing 5-(5-fluoro-1H-pyrazoles-4-base)-6-isopropyl-7-oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine- DMF (3mL) solution of 3-formonitrile HCN (150mg crude product, 0.53mmol) and 2-iodopropane (71mg, 0.42mmol) adds Cs₂CO₃(345mg, 1.06mmol).At room temperature reactant mixture is stirred 16 hours.Reactant mixture is filtered and passes through rpHPLC(Gemini C₁₈150x 25mm x 10um, 33-63%MeCN/H₂O) mixture described in purification thus to obtain white solid The title compound (25mg, 18% productivity) of body.¹H NMR(400MHz,DMSO-d₆)δ13.24(s,1H),8.39(s,1H), 8.14 (s, 1H), 4.54-4.73 (m, 1H), 2.84-2.77 (m, 1H), 1.44 (d, J=6.4Hz, 6H), 1.28 (d, J= 7.2Hz,6H)。LCMS(ESI):m/z 329.1[M+H]⁺, RT=1.23 minute (LCMS method C).

Embodiment 9

6-isopropyl-7-oxo-5-(1-(2-phenyl acrylate-2-yl)-1H-pyrazoles-4-base)-4,7-dihydro-pyrazolo [1, 5-a] pyrimidine-3-formonitrile HCN

To 6-isopropyl-7-oxo-5-(1H-pyrazole-3-yl)-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN The mixture of (200mg, 0.75mmol) and 2-phenyl propan-2-ol (2mL) adds concentrated sulphuric acid (41 μ L, 0.75mmol).Micro- Under wave radiation, reaction is heated to 100 DEG C and persistently 20 minutes.Use saturated NaHCO₃(10mL) cancellation is reacted and uses ethyl acetate (20mL) extraction.By organic facies through Na₂SO₄It is dried, filters and concentrates.By rpHPLC (Gemini C₁₈150x 25mm x 10um, 50-80%MeCN/H₂O) purification residue thus obtain required white solid product (140mg, 49% productivity).¹H NMR(400MHz,DMSO-d₆)δ13.06(s,1H),8.38(s,1H),8.31(s,1H),7.81(s,1H),7.35-7.31(m, 2H), 7.28-7.24 (m, 1H), 7.08 (d, J=7.2Hz, 2H), 3.02-2.95 (m, 1H), 1.99 (s, 6H), 1.30 (d, J= 7.2Hz,6H)。LCMS(ESI):m/z 387.1[M+H]⁺, RT=1.12 minute (LCMS method A).

Embodiment 10

6-isopropyl-7-oxo-5-(1-(pyridin-3-yl)-1H-pyrazoles-4-base)-4,7-dihydro-pyrazolo [1,5-a] Pyrimidine-3-formonitrile HCN

In a nitrogen atmosphere, 6-isopropyl-7-oxo-5-(1H-pyrazoles-4-base)-4,7-dihydro-pyrazolo [1,5-will be contained A] pyrimidine-3-formonitrile HCN (200mg, 0.75mmol), 3-iodine pyridine (306mg, 1.49mmol), CuI (7mg, 0.04mmol), L-dried meat Propylhomoserin (9mg, 0.075mmol) and K₂CO₃It is little that DMSO (5mL) mixture of (103mg, 0.75mmol) heats 16 at 120 DEG C Time.Cooled and filtered mixture also evaporates filtrate.By rpHPLC (ASB C₁₈150*25mm, 40%MeCN/H₂O) purification is remaining Thing thus obtain required white solid HCl salt product (25mg, 10% productivity).¹H NMR(400MHz,DMSO-d₆)δ 13.33 (s, 1H), 9.31 (s, 1H), 9.10 (s, 1H), 8.70 (s, 1H), 8.54 (d, J=8.4Hz, 1H), 8.42 (s, 1H), 8.16 (s, 1H), 7.80 (dd, J=8.4,4.8Hz, 1H), 3.01-2.95 (m, 1H), 1.32 (d, J=7.2Hz, 6H).LCMS (ESI):m/z 346.0[M+H]⁺, RT=1.08 minute (LCMS method C).

Embodiment 11

6-isopropyl-7-oxo-5-(1-(pyridin-4-yl)-1H-pyrazoles-4-base)-4,7-dihydro-pyrazolo [1,5-a] Pyrimidine-3-formonitrile HCN

This compound is according to similar operation as shown in Example 10, by 4-iodine pyridine with 10% productivity system Standby.¹H NMR(400MHz,DMSO-d₆):δ9.36(s,1H),9.01(brs,2H),8.45-8.43(m,3H),8.33(s,1H), 2.94-2.90 (m, 1H), 1.32 (d, J=6.8Hz, 6H).LCMS(ESI):m/z 346.1[M+H]⁺, RT=0.95 minute (LCMS method C).

Embodiment 12

6-isopropyl-7-oxo-5-(1-(pyridine-2-base)-1H pyrazoles-4-base)-4,7-dihydro-pyrazolo [1,5-a] is phonetic Pyridine-3-formonitrile HCN

At 0 DEG C at N₂Under, to containing 6-isopropyl-7-oxo-5-(1H-pyrazoles-4-base)-4,7-dihydro-pyrazolo [1,5- A] pyrimidine-3-formonitrile HCN (200mg, 0.75mmol) DMF (5mL) solution in add containing NaH (60% dispersion in mineral oil, 90mg, DMF (5mL) 2.25mmol).After stirring 30 minutes at 0 DEG C, it is dividedly in some parts 2-fluorine pyridine (109mg, 1.12mmol).Add After, gained mixture is heated 5 hours at 70 DEG C.Use saturated NH₄Cl (20mL) cancellation is reacted and uses ethyl acetate (2x 20mL) extraction.By organic layer through anhydrous Na₂SO₄It is dried, filters and concentrates.By rpHPLC (ASB C₁₈150x 25mm, 40%-70%MeCN/H₂O) purification residue thus obtain required white solid product (35mg, 14% productivity).¹H NMR (400MHz,DMSO-d₆) δ 13.29 (s, 1H), 9.01 (s, 1H), 8.55 (d, J=4.4Hz, 2H), 8.41 (s, 1H), 8.11- 8.07 (m, 2H), 8.02 (d, J=8.0Hz, 1H), 7.47-7.44 (m, 1H), 3.01-2.94 (m, 1H), 1.32 (d, J= 7.2Hz,6H)；LCMS(ESI):m/z 346.0[M+H]⁺, RT=1.24 minute (LCMS method C).

Embodiment 13

Step 1

2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan alkane-2-base)-1H-pyrazoles-1- Base) propanoate

To containing 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan alkane-2-bases)-1H-pyrazoles (5.0g, 25.8mmol) add Cs with in DMF (50mL) solution of 2 bromo 2 methyl propionic acid tertiary butyl ester (6.32g, 28.3mmol)₂CO₃ (12.59g, 38.65mmol).At room temperature reactant mixture is stirred 16 hours.Mixture is filtered and at tertbutyl ether (100mL) and H₂Distribute between O (100mL).The organic layer merged is separated, with saline washing, through anhydrous Na₂SO₄It is dried and dense Contract thus obtain crude product, by thick described in the flash silica gel chromatography purification of the use Hex containing 0-10%EtOAc Product, thus obtain required white solid product (7.0g, 81% productivity).¹H NMR(400MHz,CDCl₃)δ7.87(s, 1H),7.84(s,1H),1.81(s,6H),1.39(s,9H),1.37(s,12H)。

Step 2

2-(4-(3-cyano group-6-isopropyl-7-oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-5-base)-1H-pyrazoles- 1-yl)-2 Methylpropionic acid the tert-butyl ester

In a nitrogen atmosphere, to containing 5-chloro-6-isopropyl-7-oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-3-first Nitrile (1.0g, 4.2mmol), 2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan alkane-2-bases)-1H- Pyrazol-1-yl) propanoic acid tert-butyl ester (2.12g, 6.3mmol) and Na₂CO₃The DME:H of (890mg, 8.4mmol)₂O (2/1,30mL) Solution in add Pd (dppf) Cl₂(307mg, 0.042mmol).Reactant mixture is heated 16 hours at 110 DEG C.Cooling To room temperature, reactant mixture concentrates and passes through to use the flash silica gel chromatography purification of the DCM eluting containing 0-3%MeOH Residue thus obtain crude product, by described crude product from TBME/MeOH (5/1,20mL) recrystallization thus obtain required Brown solid (760mg, 44% productivity).¹H NMR(400MHz,DMSO-d₆)δ13.16(brs,1H),8.35(s, 1H), 8.23 (s, 1H), 7.77 (S, 1H), 2.99-2.96 (m, 1H), 1.79 (s, 6H), 1.34 (s, 9H), 1.29 (d, J= 6.8Hz,2H)。

Step 3

2-(4-(3-cyano group-6-isopropyl-7-oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-5-base)-1H-pyrazoles- 1-yl)-2 Methylpropionic acid

By 2-(4-(3-cyano group-6-isopropyl-7-oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-5-base)-1H-pyrrole Azoles-1-base) HCl/ dioxane (20mL) mixture of-2 Methylpropionic acid tertiary butyl ester (500mg, 1.22mmol) at room temperature stirs Mix 16 hours.Mixture is evaporated thus obtains can be directly used for the brown solid crude product of next step.¹H NMR (400MHz,DMSO-d₆)δ13.13(brs,1H),8.37(s,1H),8.28(s,1H),7.77(s,1H),3.01-2.94(m, 1H), 1.81 (s, 6H), 1.30 (d, J=7.2Hz, 2H).

Step 4

2-(4-(3-cyano group-6-isopropyl-7 oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-5-base)-1H-pyrazoles- 1-yl)-N, 2-dimethylpropionamide

To containing 2-(4-(3-cyano group-6-isopropyl-7 oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-5-base)-1H-pyrrole Azoles-1-base)-2 Methylpropionic acid (100mg, 0.24mmol) and DMF (2mL) solution of methylamine hydrochloride (32mg, 0.48mmol) Middle addition HATU (137mg, 0.36mmol) and DIPEA (124mg, 0.96mmol).At room temperature reactant mixture is stirred 16 Hour.By rpHPLC (Gemini C₁₈150x 25mm x 10um, 6-36%MeCN/H₂O) purification reaction mixture thus To required white solid product (28mg, 32% productivity).¹H NMR(400MHz,DMSO-d₆)δ13.02(brs,1H), 8.37 (s, 1H), 8.21 (s, 1H), 7.78 (s, 1H), 7.56 (d, J=4.0Hz, 1H), 3.03-3.00 (m, 1H), 2.61 (d, J =4.8Hz, 3H), 1.77 (s, 6H), 1.31 (d, J=6.8Hz, 6H).LCMS(ESI):m/z368.1[M+H]⁺, RT=1.08 Minute (LCMS method C).

Embodiment 14

Step 1

4-iodo-1-isopropyl-1H-pyrazoles

To iodo-1H-pyrazoles containing 4-(5g, 25.8mmol) and Cs₂CO₃The DMF (50mL) of (25.2g, 77.3mmol) stirs molten Liquid adds 2-iodopropane (5.26g, 30.9mmol).Mixture is stirred 16 hours at 10 DEG C.It is filtered to remove Cs₂CO₃.Use H₂O (50mL) dilution filtrate also extracts with EtOAc (50mL).Organic layer use water (20mL X 6) is washed.To have Machine layer is through Na₂SO₄Be dried, concentrate thus obtain required colorless oil as product (5.2g, 85% productivity).¹H NMR (400MHz,CD₃OD) δ 7.75 (s, 1H), 7.47 (s, 1H), 4.55-4.48 (m, 1H), 1.45 (d, J=6.8Hz, 6H).

Step 2

The fluoro-4-of 5-iodo-1-isopropyl-1H-pyrazoles

THF (20mL) solution that will contain 4-iodo-1-isopropyl-1H-pyrazoles (2.0g, 8.47mmol) is cooled to-78 DEG C. At-78 DEG C, LDA (8.47mL, 16.94mmol, 2M are in THF) is added dropwise in described solution, and then at-78 DEG C Lower stirring 30 minutes.Reactant mixture is cooled to-100 DEG C and in described reactant mixture, is added dropwise over N-fluoro-N-(phenyl Sulfonyl) benzsulfamide (10.7g, 33.89mmol are dissolved in 20mL THF).Reactant mixture is stirred at-78 DEG C 1 Hour.Use saturated NH₄Then Cl (50mL) cancellation reaction also extracts with EtOAc (50mL x 3).By the organic layer of merging through nothing Water Na₂SO₄It is dried, filters and concentrates thus obtain thick object, by using the quick silicon of the Hex containing 0-2%EtOAc The column chromatography eluting described thick object of glue, thus obtain required colorless oil crude product.

Step 3

5-fluoro-1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan alkane-2-base)-1H-pyrazoles

At 0 DEG C in THF (5mL) solution of iodo-1-isopropyl-1H-pyrazoles containing the fluoro-4-of 5-(400mg, 1.58mmol) Add the THF containing 1M iPrMgBr (4.7mL, 4.7mmol), and reactant is stirred 1 hour.It is subsequently adding 2-methoxyl group-4, 4,5,5-tetramethyl-1,3,2-dioxaborolan alkane (1g, 6.32mmol), and mixture is stirred 2 hours at 10 DEG C. Add saturated NH₄Cl (10mL) reacts with cancellation.Remove organic solvent the most under vacuo.Surplus with DCM (10mL x 3) extraction Under water layer.By the organic layer of merging through anhydrous Na₂SO₄It is dried, filters and concentrates thus obtain thick object, contained by use Thick object described in the flash silica gel chromatography purification of the Hex of 0-3%EtOAc, thus obtain required water white oil Shape crude product.

Step 4

5-(5-fluoro-1-isopropyl-1H-pyrazoles-4-base)-6-isopropyl-7-oxo-4,7-dihydro-pyrazolo [1,5-a] Pyrimidine-3-formonitrile HCN

In similar program as shown in Example 3, by 6-isopropyl-7-oxo-5-(1H-pyrazoles-4-base)-4,7- Dihydro-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN and 5-fluoro-1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxa boron Heterocycle pentane-2-base)-1H-pyrazoles prepares the title compound of pale solid with 14% productivity.¹H NMR(400MHz, CD₃OD) δ 8.09 (s, 1H), 7.55 (d, J=3.2Hz, 1H), 4.69-4.55 (m, 1H), 2.99-2.93 (m, 1H), 1.51 (d, J=6.8Hz, 6H), 1.36 (d, J=6.8Hz, 6H).LCMS(ESI):m/z329.1[M+H]⁺, RT=1.01 minute (LCMS side Method C).

Embodiment 15 and embodiment 16

5-(1-(Cvclopropvlmethvl)-1H-pyrazoles-5-base)-6-isopropyl-7-oxo-4,7-dihydro-pyrazolo [1,5-a] Pyrimidine-3-formonitrile HCN and 5-(1-(Cvclopropvlmethvl)-1H-pyrazole-3-yl)-6-isopropyl-7-oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN

By 6-isopropyl-7-oxo-5-(1H-pyrazole-3-yl)-4H-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN (0.224mmol, 60mg), (iodomethyl) cyclopropane (0.671mmol, 126mg) and Cs₂CO₃The DMF of (0.671mmol, 219mg) (2mL) mixture is stirred at room temperature 7 hours.Reactant mixture is filtered and filtrate by preparation HPLC purification thus is obtained To required white solid product.

First eluting peak: 5-[2-(Cvclopropvlmethvl) pyrazole-3-yl]-6-isopropyl-7-oxo-4H-pyrazolo [1,5- A] pyrimidine-3-formonitrile HCN, 5.6mg, 7.8% productivity.¹H NMR(DMSO-d₆)δ:13.63(s,1H),8.37(s,1H),7.67– 7.60 (m, 1H), 6.59 6.47 (m, 1H), 3.93 (d, J=7.0Hz, 2H), 1.37 1.09 (m, 8H), 0.51 0.38 (m, 2H),0.33–0.18(m,2H)。LCMS(ESI):m/z 323.2[M+H]⁺, RT=4.52 minute (LCMS method F).

Second eluting peak: 5-[1-(Cvclopropvlmethvl) pyrazole-3-yl]-6-isopropyl-7-oxo-4H-pyrazolo [1,5- A] pyrimidine-3-formonitrile HCN, 11.6mg, 16.1% productivity.¹H NMR(DMSO-d₆)δ:13.21(s,1H),8.36(s,1H),8.00 (d, J=2.3Hz, 1H), 6.62 (d, J=2.3Hz, 1H), 4.10 (d, J=7.1Hz, 2H), 3.13 (p, J=6.9Hz, 1H), 1.36 1.29 (m, 1H), 1.28 (d, J=7.0Hz, 6H), 0.62 0.53 (m, 2H), 0.45 0.38 (m, 2H).LCMS (ESI):m/z 323.2[M+H]⁺, RT=4.83 minute (LCMS method F).

Embodiment 17

Step 1

Tetrahydrochysene-2H-thiapyran-4-alcohol

At 0 DEG C, react mixing to the MeOH (20mL) containing dihydro-2H-thiapyran-4 (3H)-one (2.0g, 16.92mmol) Thing adds NaBH₄(1.95g, 51.64mmol).Reactant mixture is stirred 1 hour at 10 DEG C.Use saturated NH₄Cl (20mL) quenches Go out reaction, extract with EtOAc (20mL x 3).By the organic layer of merging through Na₂SO₄It is dried, filters and concentrates thus obtain required The colorless oil crude product wanted.

Step 2

Methanesulfonic acid tetrahydrochysene-2H-thiapyran-4-base ester

At 0 DEG C, to-2H-thiapyran-4-alcohol containing tetrahydrochysene (2.0g, 16.92mmol) and Et₃N (3.42g, 33.84mmol) DCM (20mL) reactant mixture in add MsCl (2.91g, 25.38mmol).Reactant mixture is stirred at 10 DEG C 2 little Time.Use saturated NaHCO₃Washing reaction mixture, extracts described reactant mixture with EtOAc (20mL x 3).By having of merging Machine layer is through Na₂SO₄It is dried, filters and concentrates thus obtain required white solid crude product.

Step 3

6-isopropyl-7-oxo-5-(1-(tetrahydrochysene-2H-thiapyran-4-base)-1H-pyrazoles-4-base)-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN

In similar program as shown in Example 6, prepare the title compound of pale solid with 12% productivity.¹H NMR(400MHz,CD₃OD)δ8.09(s.,1H),7.95(s,1H),7.68(s,1H),4.29-4.24(m,1H),3.16-3.09 (m,1H),2.96-2.85(m,2H),2.82-2.71(m,2H),2.48-2.35(m,2H),2.26-2.10(m,2H),1.37 (d, J=6.8Hz, 6H).LCMS(ESI)m/z 369.1[M+H]⁺, RT=1.01 minute (LCMS method C).

Embodiment 18

5-(1-(1,1-dioxidotetrahydro-2H-thiapyran-4-base)-1H-pyrazoles-4-base)-6-isopropyl-7-oxo-4,7-two Hydrogen pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN

At 0 DEG C, to containing 6-isopropyl-7-oxo-5-(1-(tetrahydrochysene-2H-thiapyran-4-base)-1H pyrazoles-4-base)-4, MeOH (6mL) solution of 7-dihydro-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN (65mg, 0.176mmol) is added dropwise over containing over cure Water (6mL) solution of potassium hydrogen phthalate (271mg, 0.441mmol), and reactant mixture is stirred 16 hours at 10 DEG C.In decompression Lower removing solvent.By preparation HPLC purification residue thus obtain required product as off-white solid (20mg, 29% produce Rate).¹H NMR(400MHz,CD₃OD)δ8.12(s.,1H),8.03(s,1H),7.73(s,1H),4.70-4.24(m,1H), 3.39-3.36 (m, 4H), 3.13 3.09 (m, 1H), 2.70-2.65 (m, 2H), 2.52-2.48 (m, 2H), 1.37 (d, J= 7.2Hz,6H)。LCMS(ESI):m/z 401.1[M+H]⁺, RT=0.85 minute (LCMS method C).

Embodiment 19

Step 1

4-toluene sulfonic acide (6-(methylol) pyridine-2-base) methyl ester

To containing pyridine-2, DCM (20mL) solution of 6-diyl dimethanol (1g, 7.19mmol) adds Ag₂O (2.5g, 10.78mmol) with KI (119mg, 0.72mmol).Gained mixture is cooled to-20 DEG C, and add containing TsCl (1.51g, DCM (10mL) 7.19mmol).Gained mixture is stirred at room temperature 3 hours.Reactant mixture is concentrated and passes through quickly Silica gel column chromatography (PE/EtOAc=1/1) purification thus obtain required white solid product (800mg, 40% productivity).

Step 2

4-toluene sulfonic acide (6-formylpyridine-2-base) methyl ester

To the DCM containing 4-toluene sulfonic acide (6-(methylol) pyridine-2-base) methyl ester (800mg, 2.73mmol) (10mL) solution adds MnO₂(2.37g, 27.27mmol).Gained mixture is stirred at room temperature 24 hours.By filtering Remove solid and concentrate the filtrate to be dried thus obtain required white solid product (500mg, 63% productivity).

Step 3

4-toluene sulfonic acide (E)-(6-(3-oxo but-1-ene-1-base) pyridine-2-base) methyl ester

To the toluene (20mL) containing 4-toluene sulfonic acide (6-formylpyridine-2-base) methyl ester (500mg, 1.72mmol) Solution adds 1-(dihalotriphenylphosphoranes base) acrylate-2-ketone (525mg, 1.65mmol).At 110 DEG C at N₂Under, by gained mixture Stir 16 hours, reactant mixture is concentrated and passes through flash silica gel chromatography (PE/EtOAc=3/1) purification thus obtain Required white solid product (400mg, 71% productivity).

Step 4

(E)-6-isopropyl-7-oxo-5-(1-((6-(3-oxo but-1-ene-1-base) pyridine-2-base) methyl)-1H- Pyrazoles-4-base)-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN

To containing 6-isopropyl-7-oxo-5-(1H-pyrazoles-4-base)-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN DMF (5mL) solution of (100mg, 0.3mmol) adds 4-toluene sulfonic acide (E)-(6-(3-oxo but-1-ene-1-base) pyrrole Pyridine-2-base) methyl ester (99mg, 0.3mmol), KI (5mg, 0.03mmol) and Cs₂CO₃(292mg, 0.9mmol).Gained is mixed Compound be stirred at room temperature 2 hours and by preparation HPLC purification thus obtain required yellow solid product (29mg, 23% productivity).¹HNMR(400MHz,DMSO-d₆)δ13.12(s,1H),8.36(2s,2H),7.91(m,1H),7.81(m,1H), 7.71-7.59(m,2H),7.21(m,1H),7.05(m,1H),5.60(s,2H),2.99-2.95(m,1H),2.36(s,3H), 1.30(s,6H)。LCMS(ESI):m/z 428.1[M+H]⁺, RT=0.78 minute (LCMS method E).

Embodiment 20 (method B)

6-ethyl-7-oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN

To contain 2-formoxyl methyl butyrate (3.2g, 24.6mmol) and 5-amino-1H-pyrazoles-4-formonitrile HCN (1.3g, Acetic acid (8mL) mixture 12mmol) stirs 16 hours at 80 DEG C.Reactant mixture is concentrated and uses methyl tertiary butyl ether(MTBE) (20mL) grinding residues thus obtain required white solid product (1.4g, 63% productivity)；¹H NMR(400MHz, DMSO-d₆) δ 13.36 (s, 1H), 8.37 (s, 1H), 7.85 (s, 1H), 2.42-2.48 (q, J=7.6Hz, 2H), 1.13 (t, J =7.6Hz, 3H).LCMS(ESI):m/z 189.1[M+H]⁺, RT=0.86 minute (LCMS method C).

Embodiment 21

Step 1

2-formoxyl-3,3-dimethyl butyrate acetoacetic ester

In nitrogen atmosphere, anhydrous to the tert-butyl group diethyl malonate containing 2-(500mg, 2.31mmol) at-78 DEG C DCM (5mL) solution is added dropwise over DIBAL-H (toluene solution of 1.0M, 4.62mL, 4.62mmol).By gained mixture- Stir 3 hours at 78 DEG C.Use saturated NH₄Cl aqueous solution (10mL) cancellation reactant mixture.Remove cooling bath.It is sequentially added into HCl Aqueous solution (1.0M, 10mL) and D, L-TARTARIC ACID (560mg), and make mixture be warming up to room temperature with vigorous stirring.Then will Two-phase mixture distributes between HCl/water solution (1.0M, 20mL) and DCM (20mL).Organic layer is separated, through anhydrous Na₂SO₄ It is dried, filters and concentrates thus obtain can be used for next step without the crude product being further purified.

Step 2

6-(tert-butyl group)-7-oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN

To containing 2-formoxyl-3, acetic acid (3.0mL) solution of 3-dimethyl butyrate acetoacetic ester (2.0g crude product, 2.31mmol) Middle addition 5-amino-1H-pyrazoles-4-formonitrile HCN (77mg, 0.7mmol).Gained mixture is heated 16 hours at 90 DEG C.Cooling To room temperature, reactant mixture is concentrated, then pass through and be azeotroped off acetic acid residue with toluene (10mL x 2).Gained is residual Excess methyl tertiary butyl ether(MTBE) (10mL x 2) washs thus obtains required white solid product (60mg, two step productivity 12%).¹H NMR(400MHz,DMSO-d₆)δ8.36(s,1H),7.63(s,1H),1.33(s,9H)。LCMS(ESI):m/z 217.1[M+H]⁺, RT=1.06 minute (LCMS method A).

Embodiment 22

6-isopropyl-7-oxo-5-phenyl-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN

To containing 2-benzoyl-3 Methylbutanoic acid ethyl ester (325mg, 1.39mmol, 1.5 equivalent) and 5-amino-1H-pyrrole In 2-methyltetrahydrofuran (2mL) solution of azoles-4-formonitrile HCN (100mg, 0.93mmol) add titanium tetrachloride (0.1mL, 0.87mmol).Reactant is stirred at room temperature 20 minutes, and then heats 16 hours at 80 DEG C.Reactant is cooled to Room temperature also uses saturated NaHCO₃(5mL) aqueous solution dilution.Reactant mixture EtOAc (20mL x3) is extracted and will merge Organic layer with saline (20mL) washing, through anhydrous Na₂SO₄It is dried, filters and concentrates.The own of 0 30%EtOAc is contained by using The flash silica gel chromatography purification of crude residue of alkane eluting, thus obtain required brown solid (107mg, 42% Productivity).¹H NMR(400MHz,CDCl₃)δ13.46(s,1H),8.41(s,1H),7.59-7.58(m,3H),7.53-7.52(m, 2H), 2.63-2.59 (m, 1H), 1.24 (d, J=6.8Hz, 6H).LCMS(ESI):m/z 278.9[M+H]⁺, RT=1.15 divides Clock (LCMS method A).

Embodiment 23

Step 1

3-oxo-5-phenylpentanoic acid ethyl ester

At 0 DEG C, in THF (80mL) solution containing ethyl 3-oxobutanoate (8g, 61.5mmol), it is dividedly in some parts NaH (60% oil suspension, 3g, 73.8mmol), and then stirring 30 minutes.Then by syringe add n-BuLi (29.6mL, 73.8mmol).After being cooled to-25 DEG C, add (bromomethyl) benzene (11g, 64.31mmol), and mixture is warming up to room temperature also Stir 2 hours.Use saturated NH₄Cl (200mL) aqueous solution cancellation mixture also extracts with EtOAc (100mL).By organic layer through nothing Water Na₂SO₄It is dried, filters and concentrates thus obtain crude product, by using the Flash silica of the Hex containing 0-3%EtOAc Column chromatography eluting described crude product, thus obtain required yellow oil product (9.7g, 72% productivity).¹H NMR (400MHz,CDCl₃) δ 7.25-7.29 (m, 2H), 7.16-7.20 (m, 3H), 4.16 (q, J=7.2Hz, 2H), 3.41 (s, 2H), 2.85-2.94 (m, 4H), 1.25 (t, J=7.2Hz, 3H).

Step 2

2-isopropyl-3-oxo-5-phenylpentanoic acid ethyl ester

To contain 3-oxo-5-phenylpentanoic acid ethyl ester (3g, 13.62mmol), 2-iodopropane (2.32g, 13.62mmol) and K₂CO₃DMF (30mL) mixture of (376g, 27.24mmol) is positioned in autoclave and is heated to 80 DEG C and continues 16 hours.Will Mixture filters, concentrates and passes through to use the flash silica gel chromatography purification residue of the Hex containing 0-2%EtOAc, Thus obtain required colorless liquid product (400mg, 11% productivity).¹H NMR(400MHz,CDCl₃)δ7.15-7.27(m, 5H), 4.11 (q, J=6.8Hz, 2H), 3.18 (d, J=9.6Hz, 1H), 2.78-3.19 (m, 4H), 2.40-2.78 (m, 1H), 1.21 (t, J=6.8Hz, 3H) .0.93 (d, J=6.8Hz, 3H), 0.84 (d, J=6.8Hz, 3H).LCMS(ESI):m/z 263.2[M+H]⁺, RT=1.27 minute (LCMS method A).

Step 3

6-isopropyl-7-oxo-5-phenethyl-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN

At N₂Under atmosphere, by syringe to containing 2-isopropyl-3-oxo-5-phenylpentanoic acid ethyl ester (700mg, 2.67mmol) add titanium tetrachloride with in toluene (7mL) solution of 3-amino-1H-pyrazoles-4-formonitrile HCN (433mg, 4mmol) (0.2mL, 1.6mmol), and it is then heated to 80 DEG C, continue 16 hours.Mixture is used saturated NaHCO₃(15mL) aqueous solution Cancellation also extracts with EtOAc (50mL x 2).By organic layer saline (10mL) washing merged, through anhydrous Na₂SO₄Dry, mistake Filter and concentrate.By preparation HPLC purification residue thus obtain required white solid product (15mg, 2% productivity).¹H NMR(400MHz,CDCl₃) δ 8.10 (s, 1H), 7.18-7.32 (m, 5H), 7.10 (s 1H), 3.01 (q, J=6.8Hz, 1H), 2.85-2.90 (m, 4H), 1.25 (d, J=6.8Hz, 6H).LCMS(ESI):m/z307.2[M+H]⁺, RT=1.11 minute (LCMS method A).

Embodiment 24

Step 1

3-(3-iodophenyl)-3-oxopropanoate.

In nitrogen atmosphere, to the dry toluene (100mL) containing diethyl carbonate (12.0g, 101.6mmol) at 0 DEG C Solution is dividedly in some parts NaH (60% dispersion in mineral oil, 3.25g, 81.3mmol).After stirring 5 minutes at 0 DEG C, will mixing Thing is warming up to room temperature and was added dropwise over 1-(3-iodophenyl) ethyl ketone (5.0g, 20.3mmol) in 10 minutes.By gained mixture Heat 16 hours at 110 DEG C.Reactant is cooled to 0 DEG C and uses CH₃COOH (10mL) cancellation.Add H₂O (50mL) also uses EtOAc (100mL x 2) extracts mixture.The saturated NaHCO of organic layer that will merge₃(100mL) solution washing, through anhydrous Na₂SO₄It is dried, filters and concentrates.By flash silica gel chromatography (0-5%EtOAc/PE) purification residue thus obtain institute The Red oil product (4.0g, 62% productivity) needed.¹H NMR(400MHz,CDCl₃) δ 8.28 (s, 1H), 7.92 (d, J= 8.8Hz, 1H), 7.90 (d, J=8.0Hz, 1H), 7.25-7.21 (m, 1H), 4.22 (q, J=7.2Hz, 2H), 3.95 (s, 1H), (1.27 t, J=7.2Hz, 3H).LCMS(ESI):m/z 318.8[M+H]⁺, RT=0.93 minute (LCMS method E).

Step 2

2-(3-iodobenzoyl) ethyl n-butyrate.

Molten to the acetone (20mL) including 3-(3-iodophenyl)-3-oxopropanoate (2.0g, 6.29mmol) at bottle Liquid adds K₂CO₃(3.47g, 25.16mmol), 2-iodopropane (981mg, 6.29mmol).Bottle is sealed and adds at 70 DEG C Heat 1 day.Reactant is cooled to room temperature and filters.By filtrate concentrate and will be by flash silica gel chromatography (0-5%EtOAc/ PE) purification residue thus obtain required yellow oil product (1.6g, 73% productivity).¹H NMR(400MHz,CDCl₃)δ 8.32 (s, 1H), 7.94 (d, J=8.0Hz, 1H), 7.92 (d, J=8.0Hz, 1H), 7.27-7.21 (m, 1H), 4.19-4.13 (m, 3H), 2.03 (d, J=7.2Hz, 2H), 1.20 (t, J=7.2Hz, 3H), 1.00 (t, J=7.2Hz, 3H).LCMS(ESI): m/z 346.7[M+H]⁺, RT=1.06 minute (LCMS method E).

Step 3

6-ethyl-5-(3-iodophenyl)-7-oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN

In a nitrogen atmosphere, to containing 2-(3-iodobenzoyl) ethyl n-butyrate. (500mg, 1.44mmol) and 5-amino-1H- Dry toluene (10mL) solution of pyrazoles-4-formonitrile HCN (234mg, 2.17mmol) adds TiCl₄(0.1mL, 0.87mmol).Will Reactant is stirred at room temperature 30 minutes, and then heats 16 hours at 90 DEG C.Reactant is cooled to room temperature and with saturated NaHCO₃Aqueous solution (20mL) dilutes.The organic layer extracted with EtOAc (50mL x 2) by reactant mixture and will merge is used Saline (20mL) washs, through anhydrous Na₂SO₄It is dried, filters and concentrates.By HPLC (ASB C₁₈150x 25mm, 50%MeCN/ H₂O) purification of crude residue thus obtain required titled compound as white solid (33mg, 6% productivity).¹H NMR (400MHz,CDCl₃) δ 8.05 (s, 1H), 7.92 (d, J=8.0Hz, 1H), 7.86 (s, 1H), 7.48 (d, J=8.0Hz, 1H), 7.32-7.28 (m, 1H), 2.52 (q, J=7.2Hz, 2H), 1.14 (t, J=7.2Hz, 3H).LCMS(ESI):m/z 390.9[M +H]⁺, RT=1.09 minute (LCMS method A).

Embodiment 25

3-cyano group-6-ethyl-7-oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-5-carboxylic acid

To containing 3-cyano group-6-ethyl-7-oxo-4H-pyrazolo [1,5-a] pyrimidine-5-carboxylic acid's ethyl ester (0.38425mmol, THF (1mL) suspension 100mg) adds LiOH solution (3M, 0.76M).Mixture is stirred at room temperature 4 hours.By institute State mixture dilute with water, extract with EtOAc.Water layer 1N HCl is acidified to pH 3, extracts with EtOAc (3x).To merge Organic layer through Na₂SO₄Be dried, filter, be concentrated and dried thus obtain white solid title compound (47mg, 52.7% produce Rate).¹H NMR(400MHz,DMSO-d₆) δ 8.40 (s, 1H), 2.67 (q, J=7.33Hz, 2H), 1.09 (t, J=7.31Hz, 3H)。LCMS(ESI):m/z 233.2[M+H]⁺, RT=0.37 minute (LCMS method F).

Embodiment 26

3-cyano group-6-ethyl-4-methyl-7-oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-5-Methanamide

To contain 3-cyano group-6-ethyl-4-methyl-7-oxo-pyrazolo [1,5-a] pyrimidine-5-carboxylic acid's ethyl ester (55mg, NH 0.20mmol)₄OH (28% aqueous solution, 10mL) mixture is stirred at room temperature 48 hours.Mixture is steamed by rotation Send out instrument to be concentrated to dryness.By preparation HPLC purification of crude product thus obtain white solid title compound (24.2mg, 49.2% productivity).¹H NMR(400MHz,DMSO-d₆) δ 8.50 (s, 1H), 8.41 (d, J=23.40Hz, 2H), 3.84 (s, 3H), 2.45 (q, J=7.43Hz, 2H), 1.10 (t, J=7.37Hz, 3H).LCMS(ESI):m/z 246.1[M+H]⁺, RT= 2.31 minutes (LCMS method F).

Embodiment 27

3-cyano group-6-ethyl-N, 4-dimethyl-7-oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-5-Methanamide

To contain 3-cyano group-6-ethyl-4-methyl-7-oxo-pyrazolo [1,5-a] pyrimidine-5-carboxylic acid (60mg, 0.244mmol), methylamine hydrochloride (49mg, 0.731mmol), HATU (189mg, 0.487mmol) and DIPEA (157mg, DMF (1mL) mixture 1.22mmol) is stirred at room temperature 18 hours.By preparation HPLC (containing 0.1%NH₄The 5-of OH 50%CH₃CN/H₂O) purification of crude product thus obtain the title compound (6.7mg, 10.6% productivity) of white solid.¹H NMR (400MHz,DMSO-d₆) δ 8.51 (s, 1H), 3.78 (s, 3H), 2.85 (d, J=4.70Hz, 3H), 2.80 (d, J=4.88Hz, 2H), 1.07 (t, J=7.37Hz, 3H).LCMS(ESI):m/z 260.2[M+H]⁺, RT=2.98 minute (LCMS method F).

Embodiment 28

6-ethyl-5-(3-methyl isophthalic acid, 2,4-diazole-5-base)-7-oxo-4H-pyrazolo [1,5-a] pyrimidine-3-first Nitrile

With NaH (60% dispersion in mineral oil, 34mg, 0.845mmol) andMolecular sieve (0.7g) processes the hydroxyl Han N- THF (1mL) solution of ethanamidine (60mg, 0.807mmol), and heat 1 hour at 50 DEG C.It is subsequently adding containing 3-cyano group-6-second THF (2mL) solution of base-7-oxo-4H-pyrazolo [1,5-a] pyrimidine-5-carboxylic acid's ethyl ester (100mg, 0.384mmol).Will be mixed Compound heats 4 hours at 50 DEG C.Filter to remove molecular sieve by mixture and be then concentrated to dryness.Pass through preparation HPLC Purification of crude product thus obtain the title compound (67mg, 64% productivity) of white solid.¹H NMR(400MHz,DMSO-d₆)δ 8.35 (s, 1H), 2.74 (q, J=7.30Hz, 2H), 1.09 (t, J=7.31Hz, 3H).LCMS(ESI):m/z271.2[M+H ]⁺, RT=3.87 minute (LCMS method F).

Embodiment 29

6-ethyl-5-(5-methyl isophthalic acid, 3,4-diazole-2-base)-7-oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine- 3-formonitrile HCN

To the cyano group-6-ethyl-7-oxo-4H-pyrazolo [1,5-a] pyrimidine-5-carboxylic acid containing 3-(60mg, 0.258mmol) With addition 2-chloro-1,3-dimethylimidazolinium chloride in the dichloromethane of acethydrazide (19mg, 0.258mmol) (1mL) mixture (90mg, 0.517mmol), is then added dropwise over DIPEA (133mg, 1.03mmol).Mixture is stirred at room temperature 18 little Time.Then mixture is concentrated, and then by the preparation HPLC (5%-50%CH containing 0.1% formic acid₃CN/H₂O) pure Change, thus obtain the title compound (5.6mg, 7.2% productivity) of pale solid.¹H NMR(400MHz,DMSO-d₆)δ8.30 (s, 1H), 2.77 (q, J=7.30Hz, 2H), 2.64 (s, 3H), 1.10 (t, J=7.26Hz, 3H).LCMS(ESI):m/z 271.2[M+H]⁺, RT=3.29 minute (LCMS method F).

Embodiment 30

Step 1

3-cyano group-6-ethyl-N-methoxy-. N-methyl-7-oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-5-formyl Amine

To contain 3-cyano group-6-ethyl-7-oxo-4H-pyrazolo [1,5-a] pyrimidine-5-carboxylic acid (200mg, 0.861mmol), N-methoxymethylamine hydrochloride (92mg, 0.947mmol), DIPEA (267mg, 2.0672mmol) and HATU DMF (4mL) mixture of (401mg, 4.03mmol) is stirred at room temperature 18 hours.By preparation HPLC (containing 0.1% first The 5%-50%CH of acid₃CN/H₂O) purification of crude product thus obtain the title compound (171mg, 72% productivity) of white solid.¹H NMR(400MHz,CDCl₃) δ 8.07 (s, 1H), 3.71 (s, 3H), 3.40 (s, 3H), 2.58 (d, J=7.31Hz, 2H), (1.23 t, J=7.38Hz, 3H).LCMS(ESI)m/z 276[M+H]⁺。

Step 2

6-ethyl-5-formoxyl-7-oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN

At-78 DEG C, phonetic to the cyano group-6-ethyl-N-methoxy-. N-methyl-7-oxo-4H-pyrazolo containing 3-[1,5-a] THF (3mL) solution of pyridine-5-Methanamide (170mg, 0.618mmol) is added dropwise over lithium aluminium hydride (1M THF solution, 0.678M).Mixture is stirred 1 hour at-78 DEG C, then heats to 0 DEG C and keep 2 hours at this temperature.With 25% Sodium tartrate, Soluble tartar. aqueous solution cancellation reaction.Mixture is extracted with EtOAc (6x).The Organic substance of merging is dried (Na₂SO₄), filter and concentrate.By using the flash silica gel chromatography purification of crude product of 20%MeOH/DCM eluting, thus Obtain yellow solid title compound (54mg, 40.4% productivity).LCMS(ESI)m/z 217[M+H]⁺。

Step 3

6-ethyl-5-(1H-imidazoles-2-base)-7-oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN

To containing 6-ethyl-5-formoxyl-7-oxo-4H-pyrazolo [1,5-a] pyrimidine-5-formonitrile HCN (54mg, 0.25mmol)、NH₄The suspension of OH (28% aqueous solution, 228mg, 3.75mmol) and water (0.25mL) adds Biformyl (40% aqueous solution, 181mg, 1.25mmol).Mixture is stirred at room temperature 16 hours.Then mixture is concentrated to dryness Dry, and by the preparation HPLC (5-50%CH containing 0.1% formic acid₃CN/H₂O) crude product of purification gained thus obtain The title compound (36mg, 56.7% productivity) of yellow solid.¹H NMR(400MHz,DMSO-d₆)δ8.24(s,1H),7.68 (s, 2H), 2.54 (q, J=7.36Hz, 2H), 0.94 (t, J=7.33Hz, 3H).LCMS(ESI):m/z 255.2[M+H]⁺,RT =0.62 minute (LCMS method F).

Embodiment 31

3-cyano group-6-ethyl-7-oxo-N-(2-oxo-2-phenylethyl)-4,7-dihydro-pyrazolo [1,5-a] pyrimidine- 5-Methanamide

To the cyano group-6-ethyl-7-oxo-4H-pyrazolo [1,5-a] pyrimidine-5-carboxylic acid containing 3-(200mg, 0.861mmol) With addition isobutyl chlorocarbonate (0.1463mL) in THF (2mL) solution of triethylamine (218mg, 2.15mmol).Mixture is existed Stir 1 hour under room temperature.It is subsequently adding 2-aminoacetophenone hydrochloride (163mg, 0.947mmol).By mixture at room temperature Stir 3 hours.Reactant mixture is filtered through kieselguhr, washs with EtOAc and concentrate.By preparation HPLC (containing 0.1% The 5%-50%CH of formic acid₃CN/H₂O) purification of crude product thus obtain title compound (108mg, 35.9% productivity).¹H NMR (400MHz,DMSO-d₆)δ9.22(s,1H),8.40(s,1H),8.10–8.03(m,2H),7.74–7.66(m,1H),7.58 (dd, J=7.12,8.32Hz, 2H), 4.86 (d, J=5.61Hz, 2H), 2.61 (q, J=7.26Hz, 2H), 1.10 (t, J= 7.30Hz,3H)。LCMS(ESI):m/z 350.1[M+H]⁺, RT=4.98 minute (LCMS method F).

Embodiment 32

6-ethyl-7-oxo-5-(5-phenyl azoles-2-base)-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN

To containing 3-cyano group-6-ethyl-7-oxo-N-phenacyl-4H-pyrazolo [1,5-a] pyrimidine-5-Methanamide THF (5mL) solution of (180mg, 0.515mmol) adds Burgess reagent (211mg, 0.859mmol).Mixture is existed The microwave of 120 DEG C heats 45 minutes.Mixture is concentrated and passes through preparation HPLC purification thus obtain light yellow solid Title compound (25mg, 15% productivity).¹H NMR(400MHz,DMSO-d₆)δ8.42(s,1H),8.12(s,1H),7.94– 7.87 (m, 2H), 7.62 7.54 (m, 2H), 7.51 7.44 (m, 1H), 2.91 (q, J=7.27Hz, 2H), 1.20 (t, J= 7.29Hz,3H)。LCMS(ESI):m/z 332.1[M+H]⁺, RT=6.10 minute (LCMS method F).

Embodiment 33

G02854848

6-(2,2-bis-fluoro ethyl)-7-oxo-5-phenyl-4H-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN

To the 2-methyl THF of the oxo-3-phenyl-propanoate containing 3-(0.20g, 1.04mmol) of cooling in ice bath (5mL) solution adds sodium hydride (60% dispersion in mineral oil, 0.05g, 1.2mmol), and stir the mixture for 20 minutes.To Gained solution adds trifluoromethanesulfonic acid 2,2-difluoro ethyl ester (0.24g, 1.15mmol).Then mixture is warming up to room temperature also Stir 72 hours.By reactant mixture HCl (1N) cancellation and be extracted with ethyl acetate.The Organic substance of merging is done through sodium sulfate Dry, concentrate.Crude product is converted into required product (18mg, two step productivity 5.8%) as described in Example 22.¹H NMR (400MHz,DMSO-d₆) δ 8.43 (s, 1H), 7.55 (dq, J=22.2,3.2Hz, 5H), 6.34 5.95 (m, 1H), 2.97 2.79(m,2H)。LCMS(ESI):m/z 301.2[M+H]⁺, RT=4.21 minute (LCMS method F).

Embodiment 34

6-cyclobutyl-7-oxo-5-phenyl-4H-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN

To the oxo-3-phenylpropionate containing 3-(1.00g, 5.2mmol) and the 2-of cyclobutanone (0.44g, 6.2mmol) In MeTHF (50mL) solution add titanium chloride (IV) (11.0mL, 1M DCM solution, 11mmol), be subsequently added into pyridine (2.1mL, 26mmol).Gained suspension is stirred at room temperature 20 hours.Solid and filtrate is by ethyl acetate dilute is filtered to remove Release, with saline washing, dried over sodium sulfate and concentrate.By flash silica gel chromatography (0-50%EtOAc/ heptane) after purification The residue obtained is in the presence of Pd-C (0.20g, 10%w/w on the activated carbon), at ambient temperature in ethyl acetate Hydrogenate 20 hours.Catalyst concentrated filtrate are filtered to remove thus obtain 2-cyclobutyl-3-oxo-3-phenylpropionate (0.05g, two step productivity 3.9%).Process ketone ester with 3-amino-1H-pyrazoles-4-formonitrile HCN as described in example 22 above thus obtain Product (3mg, 5.1% productivity) required for.¹H NMR(400MHz,CDCl₃)δ7.96(s,1H),7.60–7.49(m,3H), 7.47–7.38(m,2H),3.50–3.31(m,1H),2.62–2.46(m,2H),1.99–1.74(m,4H)。LCMS(ESI):m/z 291.1[M+H]⁺, RT=5.91 minute (LCMS method F).

Embodiment 35

6-cyclobutyl-7-oxo-5-(1H-pyrazoles-4-base)-4H-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN

This compound is prepared according to the similar approach shown in embodiment 34.¹H NMR(400MHz,DMSO-d₆)δ8.36 (s,1H),8.12(s,1H),7.82(s,1H),3.65–3.49(m,1H),2.74–2.55(m,2H),2.08–1.89(m,2H), 1.90–1.69(m,2H)。LCMS(ESI):m/z 281.2[M+H]⁺, RT=3.88 minute (LCMS method F).

Embodiment 36

6-cyclobutyl-5-(1-cyclohexyl pyrazoles-4-base)-7-oxo-4H-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN

To 6-cyclobutyl-7-oxo-5-(1H-pyrazoles-4-base)-4H-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN (40mg, 0.14mmol) and bromocyclohexane (46mg, 0.28mmol) mixture in add NaH (60% dispersion in mineral oil, 11mg, 0.27mmol), and by gained mixture heat 20 hours at 60 DEG C.Reactant mixture is cooled down, is acidified with HCl and uses acetic acid Ethyl ester extracts.Organic layer saline is washed, dried over sodium sulfate and concentrate.By using 0-100%EtOAc/ heptane eluting Flash silica gel chromatography purification of crude product, thus obtain required product (5mg, 10% productivity).¹H NMR (400MHz,CDCl₃) δ 7.96 (s, 1H), 7.77 (d, J=0.8Hz, 1H), 7.74 (d, J=0.7Hz, 1H), 4.27 4.12 (m, 1H), 3.72 3.58 (m, 1H), 2.80 2.64 (m, 2H), 2.23 (d, J=12.3Hz, 2H), 2.14 2.02 (m, 2H), 1.99–1.90(m,3H),1.81–1.71(m,3H),1.49–1.42(m,2H),1.35–1.15(m,2H)。LCMS(ESI):m/z 363.2[M+H]⁺, RT=5.30 minute (LCMS method F).

Embodiment 37

7-oxo-5-phenyl-6-(acrylate-2-alkynes-1-base)-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN

To the amino-1H-pyrazoles-4-formonitrile HCN containing 3-(0.20g, 1.8mmol) and 2-benzoyl amyl-4-ynoic acid ethyl esters Anhydrous 2-Me THF (20mL) solution of (0.63g, 2.7mmol) adds titanium tetrachloride (3mL 1M toluene solution, 3mmol), And gained dark orange solution is heated 2 hours at 80 DEG C.Gained reactant mixture is cooled down, is poured in water (100mL) And be extracted with ethyl acetate.Organic layer is separated, with saline washing, dried over sodium sulfate and concentrate.By Flash silica post color Spectrometry (20%-100% ethyl acetate/heptane) purification, then by ethyl acetate/heptane grinding residues thus required for obtaining Product (0.11g, 21.6% productivity).¹H NMR(400MHz,DMSO-d₆)δ13.70(s,1H),8.43(s,1H),7.70– 7.47 (m, 5H), 3.17 (d, J=2.7Hz, 2H), 2.82 (t, J=2.6Hz, 1H).LCMS(ESI):m/z 275.2[M+H]⁺, RT=4.09 minute (LCMS method F).

Embodiment 38

Step 1

1-isopropyl-1H-pyrazoles-4-formaldehyde

To the pyrazoles-4-formaldehyde containing 1H-(2.0g, 21mmol) and the DMF (10mL) of 2-iodopropane (5.32g, 31.5mmol) Solution disposably adds sodium hydride (60% dispersion in mineral oil, 0.83g, 20.7mmol).By gained mixture at room temperature Stir 2 hours, then go out with shrend and be extracted with ethyl acetate.Organic layer saline is washed, dried over sodium sulfate and concentrate. By using the flash silica gel chromatography purification residue of 0-50%EtOAc/ heptane eluting, thus obtain 1-isopropyl pyrrole Azoles-4-formaldehyde (1.2g, 42% productivity).¹H NMR(400MHz,CDCl₃) δ 9.86 (s, 1H), 7.97 (s, 2H), 4.54 (p, J= 6.7Hz, 1H), 1.55 (d, J=6.7Hz, 6H).

Step 2

3-(1-isopropyl-1H-pyrazoles-4-base)-3-oxopropanoate

LDA (7.24mL, 2M THF/ heptan is added in ethyl acetate (1.28g, the 14.5mmol) solution be cooled to-78 DEG C Alkane/ethylbenzene solution, 14.4mmol), and mixture is stirred 20 minutes at-78 DEG C.The isopropyl Han 1-is added in this mixture Mixture is also stirred for 20 minutes by THF (3mL) solution of base pyrazoles-4-formaldehyde (1.00g, 7.24mmol).Use saturated chlorination Mixture is also warming up to room temperature by ammonium salt solution cancellation reactant mixture.Mixture is extracted with ethyl acetate.By organic layer salt Water washing, dried over sodium sulfate and concentrate.Dissolve residue with DCM (100mL) and disposably add MnO₂(5.0g).Will mixing Thing is stirred at room temperature 20 hours.It is filtered to remove MnO by Celite pad₂And filtrate is concentrated.Pass through flash chromatography on silica gel Method (0-100%EtOAc/ heptane) purification of crude product thus obtain required product (0.70g, 40% productivity).¹H NMR (400MHz,CDCl₃) δ 7.99 (d, J=0.6Hz, 1H), 7.93 (d, J=0.7Hz, 1H), 4.52 (p, J=6.7Hz, 1H), 4.20 (q, J=7.1Hz, 2H), 3.75 (s, 2H), 1.53 (d, J=6.7Hz, 6H), 1.26 (t, J=7.1Hz, 3H).

Step 3

5-(1-isopropylpyrazol-4-base)-6-(1-methyl Propargyl)-7-oxo-4H-pyrazolo [1,5-a] is phonetic Pyridine-3-formonitrile HCN

By 3-(1-isopropylpyrazol-4-base)-3-oxo-propionate (0.20g, 0.89mmol), 3-bromine butyl-1-alkynes (0.13g, 0.98mmol) and the potassium carbonate (0.18g, 1.33mmol) mixture in acetone (30mL) heat 20 at 50 DEG C Hour.Reactant mixture is cooled down and solid is filtered to remove.Gained filtrate is concentrated and crude product is dissolved in acetic acid second In ester, successively with water and saline washing.By dried over sodium sulfate for organic layer and concentrate.Crude product is dissolved in 2-Me THF (10mL) in and add 5-amino-1H-pyrazoles-4-formonitrile HCN (0.050g, 0.5mmol), it is subsequently added into titanium tetrachloride (2.6mL, 1M Toluene solution).Mixture is heated 2 hours at 80 DEG C.Reactant mixture is cooled down, with water and diluted ethyl acetate.To have The washing of machine layer saline, dried over sodium sulfate and concentrate.Pure by flash silica gel chromatography (0-100%EtOAc/ heptane) Change, then by ethyl acetate grinding residues thus obtain required product (35mg, two step productivity 12%).¹H NMR (400MHz,DMSO-d₆) δ 8.07 (d, J=19.6Hz, 1H), 8.02 (s, 1H), 7.69 (s, 1H), 4.58 (p, J=6.7Hz, 1H), 4.06 (d, J=8.0Hz, 1H), 2.74 (d, J=2.6Hz, 1H), 1.51 (d, J=7.1Hz, 3H), 1.47 (d, J= 6.7Hz,6H)。LCMS(ESI):m/z 321.2[M+H]⁺, RT=4.00 minute (LCMS method F).

Embodiment 39

Step 1

2-benzoyl-3-cyclopropyl-butyrate ethyl ester

To in ice bath cooling the THF containing CuCl (20mg) (2mL) suspension in add cyclopropyl magnesium bromide (15mL, 0.5M THF solution), and suspension is stirred 10 minutes.Be added dropwise over containing 2-benzoyl but-2-ene acetoacetic ester (0.50g, 5mL THF solution 2.3mmol), and reactant mixture is stirred 1 hour at 0 DEG C.Then by reactant mixture HCl/water Solution cancellation also uses diluted ethyl acetate.Organic layer is separated, with saline washing, dried over sodium sulfate and concentrate.By quickly Silica gel column chromatography purification (0-50%EtOAc/ heptane) thus obtain required product (0.45g, 75% productivity).¹H NMR (400MHz,CDCl₃)δ8.09–7.96(m,2H),7.62–7.51(m,1H),7.54–7.38(m,2H),4.43–4.28(m, 1H), 4.22 4.05 (m, 2H), 1.86 1.69 (m, 1H), 1.19 (t, J=7.1Hz, 3H), 1.09 (dd, J=36.8, 6.7Hz,3H),0.80–0.03(m,4H)。

Step 2

6-(1-cyclopropylethyl)-7-oxo-5-phenyl-4H-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN

The similar program shown in embodiment 37 is used to synthesize this compound.¹H NMR(400MHz,DMSO-d₆)δ13.47 (s,1H),8.40(s,1H),7.64–7.39(m,5H),1.54–1.44(m,2H),1.35–1.31(m,3H),0.43–0.35 (m,1H),0.26–0.24(m,1H),0.18–0.15(m,1H)。LCMS(ESI):m/z 305.2[M+H]⁺, RT=4.99 minute (LCMS method F).

Embodiment 40

5-([1,1'-xenyl]-3-base)-6-ethyl-7-oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN

By 5-(3-bromophenyl)-6-ethyl-7-oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN (0.060g, 0.19mmol), phenylboric acid (0.030g, 0.23mmol), double (triphenyl phasphine) palladium (II) (0.02g) of dichloro and sodium carbonate (0.10g, mmol) mixture in dioxane/water (2mL/0.5mL) heats 20 minutes in the microwave reactor of 110 DEG C. Reactant mixture HCl is acidified and is extracted with ethyl acetate.Organic layer saline is washed, dried over sodium sulfate and concentrate. By flash silica gel chromatography (20%-100%EtOAc/ heptane) purification, and use ethyl acetate/heptane grinding residues Thus obtain required product (0.01g, 4% productivity).¹H NMR(400MHz,DMSO-d₆) δ 8.26 (t, J=1.8Hz, 1H), 8.12 (s, 1H), 8.03 (dt, J=7.9,1.4Hz, 1H), 7.77 7.65 (m, 3H), 7.59 7.46 (m, 3H), 7.47 7.37(m,1H),6.29(s,1H)。LCMS(ESI):m/z 313.2[M+H]⁺, RT=5.35 minute (LCMS method F).

Embodiment 41

6-ethyl-5-(3-((4-fluorophenyl) amino) phenyl)-7-oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-3- Formonitrile HCN

By 5-(3-bromophenyl)-6-ethyl-7-oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN (0.10g, 0.29mmol), 4-fluoroaniline (0.065mg, 0.50mmol), Pd₂(dba)₃(20mg) with tert-BuX-Phos (20mg), cesium carbonate (0.29g, 0.87mmol) mixture in dioxane (5mL) heats 5 hours at 110 DEG C.Only observe the required of trace Product.Therefore, then add in this mixture (chlorine [BrettPhos] [2-(2-amino-ethyl phenyl]-palladium (II)] }/ (mole PdP/P=1:1 (40mg) also reheats 15 hours at 110 DEG C [BrettPhos] mixture.Reactant mixture is used HCl is acidified and is extracted with ethyl acetate.Organic layer is separated and with saline washing, dried over sodium sulfate and concentrate.By quickly Silica gel column chromatography (0-100%DCM/EtOAc) purification, and by ethyl acetate/heptane grinding residues thus needed for obtaining The product (20mg, 18.5% productivity) wanted.¹H NMR(400MHz,DMSO-d₆) δ 13.44 (s, 1H), 8.38 (d, J=3.3Hz, 2H), 7.39 (t, J=7.9Hz, 1H), 7.19 7.07 (m, 5H), 6.95 6.85 (m, 1H), 2.34 (q, J=7.3Hz, 2H), 1.01 (t, J=7.3Hz, 3H).LC/MS (ESI): m/z=374.2 [M+H]⁺, RT=5.16 minute (LCMS method F).

Embodiment 42

6-isopropyl-7-oxo-5-(3-(2-oxo-pyrrolidine-1-base) phenyl)-4,7-dihydro-pyrazolo [1,5-a] is phonetic Pyridine-3-formonitrile HCN

Microwave tube is included 5-(3-bromophenyl)-6-isopropyl-7-oxo-4H-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN (0.168mmol, 60mg), 2-Pyrrolidone (0.588mmol, 50mg), BrettPhos (0.0168mmol, 9.2mg), BrettPhos pre-catalyst (0.0168mmol, 13.7mg) and Cs₂CO₃Isosorbide-5-Nitrae-the dioxane (2mL) of (0.336mmol, 109mg) Mixture N₂Purge 2 minutes, then heat 40 minutes by the seal of tube and in the microwave of 140 DEG C.Mixture is passed through diatom Soil filters, washs with EtOAc, concentrate.By preparation HPLC purification of crude product thus obtain required white solid product (29mg, 47% productivity).¹H NMR(DMSO-d₆)δ:13.43(s,1H),8.37(s,1H),7.88–7.78(m,2H),7.56 (t, J=7.9Hz, 1H), 7.25 (d, J=7.5Hz, 1H), 3.88 (t, J=7.0Hz, 2H), 2.65 (p, J=6.9Hz, 1H), 2.57 2.52 (m, 2H), 2.16 2.03 (m, 2H), 1.24 (d, J=6.9Hz, 6H).LCMS(ESI):m/z 362.2[M+H ]⁺, RT=4.27 minute (LCMS method F).

Embodiment 43

Step 1

5-nitro-[1,1'-xenyl]-3-carboxylic acid, ethyl ester

5-bromo-3-ethyl nitrobenzoate (5.0g, 18mmol), phenylboric acid (2.7g, 21mmol), double (triphen will be contained Phosphine) palladium (II) dichloride (0.63g, 0.89mmol) and sodium carbonate (7.6g, 72mmol) be in dioxane/water (50:10mL) Mixture heat 20 hours at 90 DEG C.Reactant mixture is cooled down, dilute with water being extracted with ethyl acetate.By organic layer With saline washing, dried over sodium sulfate and concentrate.Produced by flash silica gel chromatography (10-50%EtOAc/ heptane) purification of crude Thing thus obtain required product (4.1g, 85% productivity).¹H NMR(400MHz,CDCl₃) δ 8.82 (dd, J=2.2, 1.4Hz, 1H), 8.67 8.53 (m, 2H), 7.76 7.62 (m, 2H), 7.60 7.41 (m, 3H), 4.48 (q, J=7.2Hz, 2H), 1.46 (t, J=7.1Hz, 3H).

Step 2

5-amino-[1,1'-xenyl]-3-formaldehyde

To the 2-Me THF containing 3-nitro-5-phenyl-ethyl benzoate (1.0g, 2.1mmol) of cooling at 0 DEG C (20mL) solution adds LAH (2.9mL 1M THF solution, 2.9mmol), and mixture was warming up to room temperature in 20 minutes. With saturated ammonium chloride cancellation reactant mixture.By Celite pad solids removed by filtration and by dried over sodium sulfate for filtrate and dense Contracting.Dissolve residue with DCM (50mL) and disposably add MnO₂(2.0g).Mixture is stirred at ambient temperature 72 little Time.Make reactant mixture pass through Celite pad concentrated filtrate thus obtain pale solid (0.30g, 34% productivity).¹H NMR(400MHz,CDCl₃) δ 10.04 (s, 1H), 7.91 (t, J=1.9Hz, 1H), 7.87 (s, 1H), 7.79 (t, J=1.6Hz, 1H),7.65–7.59(m,2H),7.49–7.44(m,2H),7.42–7.36(m,1H),6.70(s,1H),1.56(s,9H)。

Step 3

5-(3-amino-5-phenyl-phenyl)-7-oxo-4H-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN

The program shown in embodiment 20 is used to prepare described compound.¹H NMR(400MHz,DMSO-d₆)δ8.43(s, 1H),7.77–7.67(m,2H),7.56–7.45(m,2H),7.44–7.35(m,2H),7.23(s,1H),7.12(s,1H), 6.25(s,1H)。LCMS(ESI):m/z 328.1[M+H]⁺, RT=4.19 minute (LCMS method F).

Embodiment 44

N-[3-(3-cyano group-7-oxo-4H-pyrazolo [1,5-a] pyrimidine-5-base)-5-phenyl-phenyl] acetamide

To containing 5-(3-amino-5-phenyl-phenyl)-7-oxo-4H-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN (100mg, DCM (5mL) 0.30mmol) and the solution of DIPEA (0.11mL, 0.61mmol) add chloroacetic chloride (48mg, 0.61mmol). Reactant mixture is stirred 1 hour.Reactant mixture with DCM dilution and is washed with HCl, the most successively with water and salt washing Wash.By dried over sodium sulfate for organic layer and concentrate.By rpHPLC purification gained residue thus obtain required product (15mg, 13% productivity).¹H NMR(400MHz,DMSO-d₆) δ 10.28 (s, 1H), 8.35 (d, J=17.1Hz, 1H), 8.15 8.08(m,1H),8.01(s,1H),7.79–7.68(m,3H),7.56–7.46(m,2H),7.46–7.39(m,1H),6.26(s, 1H),2.12(s,3H)。LCMS(ESI):m/z 370.4[M+H]⁺, RT=4.44 minute (LCMS method F).

Embodiment 45 (method C)

6-bromo-7-oxo-5-phenyl-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN

To containing 7-oxo-5-phenyl-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN (1.00g, 4.2mmol) DMF (5mL) suspension adds NBS (0.75g, 4.2mmol).Mixture is stirred at room temperature 15 minutes, and then uses water Dilution.Precipitate is collected by filtration, is washed with water and be dried 20 hours in the vacuum drying oven of 50 DEG C thus obtain institute The product (0.70g, 52% productivity) needed.¹H NMR(400MHz,DMSO-d₆):δ8.44(s,1H),7.67–7.51(m,5H)。 LCMS(ESI):m/z 317.1[M+H]⁺, RT=3.48 minute (LCMS method F).

Embodiment 46

6-(2-furyl)-5-methyl-7-oxo-4H-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN

6-bromo-5-methyl-7-oxo-4H-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN (0.10g, 0.39mmol), 2-will be contained Double (triphenyl phasphine) palladium (II) (0.014g) of furyl boronic acid (0.05g, 0.47mmol), dichloro and sodium carbonate (0.16g, 1.6mmol) mixture in ethanol/water (2mL/0.5mL) mixture is heated to 150 DEG C in microwave reactor, continues 20 Minute.Reactant mixture HCl is acidified and is extracted with ethyl acetate.Organic layer is separated, washs with saline, do through sodium sulfate Dry and concentrate.By flash silica gel chromatography (20-100% ethyl acetate/heptane) purification and grind by ethyl acetate/heptane Residue thus obtain required product (0.01g, 11.2% productivity).¹H NMR(400MHz,DMSO-d₆)δ8.30(s, 1H),8.12(s,1H),7.68–7.61(m,1H),6.60–6.48(m,2H),2.30(s,3H).LC/MS (ESI): m/z= 241.2[M+H]⁺, RT=3.21 minute (LCMS method F).

Embodiment 47 (method D)

6-isopropyl-7-oxo-5-(phenyl amino)-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN

To contain 5-chloro-6-isopropyl-7-oxo-4H-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN (60mg, 0.253mmol), Aniline (71mg, 0.76mmol), BrettPhos (14mg, 0.025mmol), BrettPhos pre-catalyst (20mg, 0.025mmol) and Isosorbide-5-Nitrae-dioxane (2mL) the mixture N of tBuONa (75mg, 0.76mmol)₂Purge 2 minutes, then exist The microwave reactor of 140 DEG C heats 20 minutes.Mixture is filtered to remove solid.Filter cake is washed with EtOAc.By merge Filtrate concentrates.By preparation HPLC purification of crude product thus obtain white solid title compound (8.2mg, 11% produce Rate).¹H NMR(400MHz,DMSO-d₆) δ 12.93 (s, 1H), 8.56 (s, 1H), 8.21 (s, 1H), 7.30 (t, J=7.76Hz, 2H), 7.09 (d, J=14.17Hz, 2H), 6.98 (s, 1H), 3.18 3.00 (m, 1H), 1.29 (d, J=6.87Hz, 6H). LCMS(ESI):m/z 294.1[M+H]⁺, RT=5.3 minute (LCMS method F).

Embodiment 48

6-isopropyl-7-oxo-5-(piperidin-1-yl)-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN

To contain 5-chloro-6-isopropyl-7-oxo-4H-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN (160mg, 0.676mmol, 20mg), piperidines (173mg, 2.03mmol), RuPhos (32mg, 0.0676mmol), RuPhos pre-catalyst (52mg, 0.0676mmol) and THF (5mL) the mixture N of tBuONa (200mg, 2.03mmol)₂Purge 2 minutes, then at 140 DEG C Microwave reactor in heat 15 minutes.Mixture is filtered to remove solid.Filter cake is washed with EtOAc.The filtrate that will merge Concentrate.By the crude product of preparation HPLC purification gained thus obtain pale solid title compound (10.1mg, 5.2% productivity).¹H NMR(400MHz,DMSO-d₆) δ 8.10 (s, 1H), 4.22 4.09 (m, 1H), 3.94 (d, J=3.29Hz, 1H), 3.63 (m, 2H), 3.54 3.42 (m, 1H), 2.17 (m, 1H), 1.73 1.48 (m, 4H), 1.15 (d, J=6.78Hz, 3H), 0.66 (d, J=6.84Hz, 3H).LCMS(ESI):m/z 286.2[M+H]⁺, RT=5.76 minute (LCMS method F).

Embodiment 49

Step 1

5-bromo-6-isopropyl-7-oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN

To chloro-6-isopropyl-7-oxo-4H-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN containing 5-(200mg, 0.845mmol) EtCN (4mL) suspension in be added dropwise over TMSBr (1.29g, 8.45mmol).Then mixture is heated at 115 DEG C 17 Hour.React with frozen water cancellation, extract with EtOAc (3x).By the Organic substance of merging through Na₂SO₄It is dried, filters and concentrates.Pass through Flash silica gel chromatography (containing the 0-10%MeOH/DCM of 1% formic acid) purification of crude product thus obtain the mark of pale solid Topic compound (129mg, 54.3% productivity).LCMS(ESI)m/z 283.1[M+H]⁺。

Step 2

6-isopropyl-7-oxo-5-phenoxy group-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN

To contain 5-bromo-6-isopropyl-7-oxo-4H-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN (80mg, 0.28mmol), Phenol (81mg, 0.85mmol), CuI (5mg, 0.028mmol), trans-N, N '-dimethyl hexamethylene-1,2-diamidogen (8mg, 0.056mmol) and K₃PO₄DMSO (2mL) the mixture N of (187mg, 0.85mmol)₂Purge 2 minutes, then micro-at 150 DEG C Ripple reactor heats 20 minutes.Mixture is filtered.Filter cake is washed with EtOAc.The filtrate merged is concentrated.Pass through preparative HPLC is (containing 0.1%NH₄The 5%-50%CH of OH₃CN/H₂O) purification of crude product thus obtain the title compound of pale solid Thing (14mg, 17% productivity).¹H NMR(400MHz,DMSO-d₆)δ7.97(s,1H),7.38–7.29(m,2H),7.10-7.06 (m, 2H), 7.02 6.97 (m, 2H), 3.35-3.31 (m, 1H), 1.24 (d, J=6.81Hz, 6H).LCMS(ESI):m/z 295.2[M+H]⁺, RT=5.73 minute (LCMS method F).

Also the general synthetic method (Syn.Met.) shown in using and general LCMS method are prepared with compounds of Formula I.

Embodiment 433

The synthesis of 2-acetyl group ethyl valerate

2-acetyl group ethyl valerate is synthesized according to Beddow etc., Org.Biomol.Chem.5:2812-2825 (2007).? Be added dropwise in THF (150mL) solution containing t-BuOK (11.8g, 0.11mol) at 0 DEG C ethyl 3-oxobutanoate (13g, 0.1mol), after stirring 30 minutes, it is added dropwise over 1-N-Propyl Bromide (12.3g, 0.1mmol) and mixture is refluxed 16 hours.Will be anti- Mixture shrend is answered to go out, with EtOAc (100mL X 2) extraction, by the organic layer of merging through anhydrous Na₂SO₄It is dried, evaporates, leads to Cross column chromatography eluting thus obtain expecting compound 2-acetyl group ethyl valerate (8.5g, 49%) of colorless oil.m/z (ESI)173[M+H]⁺。

Embodiment 434

By the method similar with embodiment 433, suitable parent material is used to prepare the compound in table 2.

Table 2.

Embodiment 435

The synthesis of 2-ethyl-4-methoxyl group-ethyl 3-oxobutanoate

2-ethyl-4-methoxyl group-ethyl 3-oxobutanoate is prepared according to WO 98/43968.To contain zinc (2g, 30mmol), The toluene (50mL) of the mercuric chloride of methoxyacetonitrile (1.42g, 20mmol) and catalytic amount is heated to backflow.It is added dropwise over 2-bromine fourth Acetoacetic ester (5.85g, 30mmol), then proceedes to reflux 1 hour and be cooled to room temperature.Add 10% aqueous sulfuric acid (16.5mL), and by organic layer separate.It is extracted with ethyl acetate further water layer and washs merging with water and saturated sodium bicarbonate Organic layer, be then dried through anhydrous magnesium sulfate and concentrate in a vacuum.By column chromatography eluting residue thus obtain Huang Color oil product (1.7g, 45%).¹H NMR(300MHz,CDCl₃) δ 4.14 (q, J=7.2Hz, 2H), 4.07 (d, J= 3.6Hz, 2H), 3.45 (t, J=7.2Hz, 1H), 3.37 (s, 3H), 1.85 (m, 2H), 1.22 (t, J=7.2Hz, 3H) .0.90 (t, J=7.5Hz, 3H)；m/z(ESI)189[M+H]⁺。

Embodiment 436

By the method similar with embodiment 435, use suitable parent material to prepare and separate the compound in table 3.

Table 3.

Embodiment 437

The synthesis of 2-ethyl-3-oxosuccinic acid diethylester

2-ethyl-3-oxosuccinic acid two is prepared according to Soloway etc., J.Org.Chem.69:2677-2678 (1947) Ethyl ester.In ether (100mL) mixture containing NaH (60%, 12g, 300mmol) and ethyl oxalate (43.8g, 300mmol) Add ethyl n-butyrate. (18g, 150mmol).Reactant mixture is refluxed overnight.After cooling to room temperature, water is added, by mixture Extract with EtOAc.By organic layer through Na₂SO₄It is dried and is evaporated in vacuo.By column chromatography eluting residue thus obtain lightweight Oil 2-ethyl-3-oxosuccinic acid diethylester (8g, 24%).m/z(ESI)217[M+H]⁺。

Embodiment 438

The synthesis of 2-ethyl-6-methoxyl group-3-oxo ethyl hexanoate

2-ethyl-6-methoxyl group-3-oxo ethyl hexanoate is prepared according to WO2006124490.

The synthesis of 6-methoxyl group-3-oxo ethyl hexanoate

At 0 DEG C, in THF (50mL) solution containing ethyl 3-oxobutanoate (1.3g, 10mol) add NaH (60%, 480mg, 12mmol).At N₂Under stir after 0.5 hour at 0 DEG C, at 0 DEG C, add n-BuLi (4mL, 10mmol) then Mixture solution is cooled to-25 DEG C.After adding 1-bromo-2-Ethyl Methyl Ether (1.39g, 10mmol), mixture solution is existed It is stirred overnight under room temperature.Mixture is evaporated in vacuo, by column chromatography eluting thus obtain 6-methoxyl group-3-oxo caproic acid second Ester (0.65g, 34.5%).m/z(ESI)211[M+Na]⁺。

The synthesis of 2-ethyl-6-methoxyl group-3-oxo ethyl hexanoate

Add in THF (50mL) solution of the methoxyl group-3-oxo ethyl hexanoate containing 6-(650mg, 3.45mmol) at 0 DEG C Enter^tBuOK (406mg, 3.63mmol), and then mixture solution is stirred 30 minutes at 0 DEG C, then reflux overnight.Will be mixed Compound be evaporated in vacuo, by column chromatography eluting thus obtain 2-ethyl-6-methoxyl group-3-oxo ethyl hexanoate (400mg, 53.6%).m/z(ESI)217[M+H]⁺。

Embodiment 439

The synthesis of 6-cyclopropyl-5-methyl-7-oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN

The synthesis of 2-cyclopropyl-3-oxo butyronitrile

At N₂Under at-78 DEG C, in THF (10mL) solution of the cyclopropyl acetonitrile containing 2-(1.17g, 14.4mmol) dropwise Add LDA (8.7ml, 17.3mmol).After stirring 60 minutes, at-78 DEG C, it is added dropwise over (CH₃O)₂O (1.12g, 14.4mmol) And mixture is stirred at ambient temperature 2 hours.By reactant mixture HCl (2N) aqueous solution cancellation, use ethyl acetate (30ml X 3) extracts, by the organic layer of merging through anhydrous Na₂SO₄It is dried and evaporates, by column chromatography eluting thus obtain Huang 2-cyclopropyl-3-oxo the butyronitrile of color oily.m/z(ESI)124[M+H]⁺。

The synthesis of 2-cyclopropyl-ethyl 3-oxobutanoate

At 0 DEG C, dropwise add in EtOH (10mL) solution of the cyclopropyl-3-oxo butyronitrile containing 2-(600mg, 5mmol) Enter chloroacetic chloride (3mL).After stirring 16 hours, remove EtOH, add in mixture dense HCl (1mL) and EtOH (10mL) and Stir 4 hours at 40 DEG C.Mixture shrend is gone out and uses ethyl acetate (20mL X 3) to extract, by the organic layer of merging through nothing Water Na₂SO₄It is dried and evaporates, by column chromatography eluting thus obtain the 2-cyclopropyl-ethyl 3-oxobutanoate of yellow oily (30mg, 10%).m/z(ESI)171[M+H]⁺。

Embodiment 440

The synthesis of 5-amino-3-ethyl-1H-pyrazoles-4-formonitrile HCN

5-amino-3-second is prepared in the way of substantially similar with described in WO2005070916 and US2006135526 Base-1H-pyrazoles-4-formonitrile HCN.

The synthesis of 2-(1-methoxyl group propylidene) Cyanoacetyl-Cyacetazid

The mixture of Cyanoacetyl-Cyacetazid (180g, 1.02mol) and triethyl orthopropionate (66g, 1mol) is refluxed 3 hours.Will be anti- Answer mixture to distill under vacuo thus obtain the expecting compound 12-1-a (60g, 40%) of pale yellowish oil.¹H NMR (300MHz,CDCl₃) δ 4.46 (q, J=6.9Hz, 2H), 2.65 (q, J=7.5Hz, 2H), 1.45 (t, J=6.9Hz, 3H), 1.26 (t, J=7.5Hz, 3H).

The synthesis of 5-amino-3-ethyl-1H-pyrazoles-4-formonitrile HCN

At 0 DEG C, will contain EtOH (50mL) solution of 2-(1-methoxyl group propylidene) Cyanoacetyl-Cyacetazid (10g, 0.067mol) by It is added dropwise to EtOH (100mL) solution containing a hydrazine hydrate (6.8ml, 0.134mol), continues 30 minutes.Stir at 90 DEG C After 3 hours, mixture is concentrated and by column chromatography eluting thus obtain the expecting compound 5-amino-3-second of yellow solid Base-1H-pyrazoles-4-formonitrile HCN (5g, 60% productivity).¹H NMR(300MHz,CDCl₃) δ 4.40 (s, 2H), 2.69 (q, J= 7.5Hz, 2H), 1.29 (t, J=7.5Hz, 3H).

Embodiment 441

General procedure

By the mixture of cyano pyrazole (0.86mmol), 'beta '-ketoester (293mg, 1.72mmol) and acetic acid (3mL) at 80 DEG C Lower stirring 1.5 hours.Mixture is cooled to room temperature.Remove solvent under vacuo.By silica gel column chromatography purification residue Thus obtain required compound.

The general procedure in above-described embodiment 441 and suitable parent material is used to prepare the compound in table 4.

Table 4.

Embodiment 442

The synthesis of 4-methyl-9-oxo-4,5,6,7,8,9-hexahydro pyrazolo [5,1-b] quinazoline-3-formonitrile HCN

By 9-oxo-4,5,6,7,8,9-hexahydro pyrazolo [5,1-b] quinazolines-3-formonitrile HCN (50mg, 0.23mmol) are molten Solution, in DMF (1mL), adds potassium carbonate (63mg, 0.46mmol), is subsequently added into iodomethane (36mg, 0.26mmol).By mixture It is stirred at room temperature overnight, then dilutes with water (10mL) and extract with EtOAc (5mL X 3).The organic layer of merging is dried And be concentrated to dryness.By residue from methanol recrystallization thus obtain 12-3 (25mg, 47%).¹H NMR(300MHz, CDCl₃)δ8.07(s,1H),3.94(s,3H),2.69(m,4H),1.92(m,2H),1.76(m,2H)；m/z(ESI)229[M+ H]⁺。

By the method similar with embodiment 442, use suitable parent material to prepare and separate 6-ethyl-4,5-diformazan Base-7-oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN.

Embodiment 443

4-(2-bromoethyl)-6-ethyl-5-methyl-7-oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN Synthesis

At ambient temperature, in water (20mL) solution of tetrabutyl ammonium bromide (557mg, 1.73mmol), NaOH is added (76mg, 1.9mmol), is subsequently added into containing 6-ethyl-5-methyl-7-oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-3-first The CHCl of nitrile (350mg, 1.73mmol)₃(20mL), mixture is continued stirring 10 minutes.Separate organic facies, use CHCl₃ (10mL) aqueous phase extracted.By the organic facies of merging through anhydrous Na₂SO₄It is dried, evaporates, to obtain white solid.Use CH₃CN (10mL) dissolved solid, then dissolves with glycol dibromide (360mg, 2mmol).Continue mixture at a reflux temperature to stir Mix 16 hours, then concentrate and by column chromatography eluting thus obtain 4-(2-bromoethyl)-6-ethyl-5-methyl-7-oxo- 4,7-dihydro-pyrazolos [1,5-a] pyrimidine-3-formonitrile HCN (200mg, 40%).m/z(ESI)309[M+H]⁺。

Embodiment 444

4-(2-(dimethylamino) ethyl)-6-ethyl-5-methyl-7-oxo-4,7-dihydro-pyrazolo [1,5-a] is phonetic The synthesis of pyridine-3-formonitrile HCN

To containing 4-(2-bromoethyl)-6-ethyl-5-methyl-7-oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-3-first DMF (10mL) solution of nitrile (200mg, 0.65mmol) adds potassium carbonate (446mg, 3.24mmol), and is subsequently added hydrochloric acid Dimethylamine (155mg, 1.94mmol).Mixture is stirred at room temperature overnight, then dilutes with water (10mL) and use EtOAc (10mL X 3) extracts.By the organic layer Na of merging₂SO₄It is dried, concentrates and passes through column chromatography eluting, thus obtain 4-(2- (dimethylamino) ethyl)-6-ethyl-5-methyl-7-oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN (12mg, 10%).¹H NMR(300MHz,CD₃OD) δ 8.29 (s, 1H), 4.52 (t, J=7.2Hz, 2H), 2.83 (t, J=7.2Hz, 2H), 2.72 (q, J=7.5Hz, 2H), 2.61 (s, 3H), 2.39 (s, 6H) 1.15 (t, J=7.5Hz, 3H)；m/z(ESI)274[M+H ]⁺。

Embodiment 445

The synthesis of 9-methoxyl group-5,6,7,8-tetrahydro-pyrazole also [5,1-b] quinazoline-3-formonitrile HCN

The synthesis of 9-chloro-5,6,7,8-tetrahydro-pyrazole also [5,1-b] quinazoline-3-formonitrile HCN

In a nitrogen atmosphere, to containing 9-oxo-4,5,6,7,8,9-hexahydro pyrazolo [5,1-b] quinazoline-3-formonitrile HCNs The anhydrous POCl of (1.0g, 4.6mmol)₃(20mL) solution adds pyridine (0.2mL), heat the mixture to 110 DEG C, mistake Night.After being cooled to room temperature, remove solvent under vacuo, and by silica gel column chromatography purification residue thus obtain required Chloro-5,6,7, the 8-tetrahydro-pyrazoles of compound 9-also [5,1-b] quinazoline-3-formonitrile HCN (0.6g, 56% productivity).¹H NMR (300MHz,CDCl₃)δ8.36(s,1H),3.10(m,2H),2.93(m,2H),1.96(m,4H)。

The synthesis of 9-methoxyl group-5,6,7,8-tetrahydro-pyrazole also [5,1-b] quinazoline-3-formonitrile HCN

At room temperature, will contain chloro-5,6,7, the 8-tetrahydro-pyrazoles of 9-also [5,1-b] quinazoline-3-formonitrile HCN (100mg, 0.43mmol) MeOH (4mL) mixture with MeONa (48mg, 0.86mmol) stirs 1.5 hours, and uses NH₄Cl cancellation is anti- Should, and extract with DCM (50mL × 3).By organic layer saline washing, through Na₂SO₄It is dried, concentrates in a vacuum, and by system Standby type thick layer chromatography purification of crude product thus obtain required compound as white solid 9-methoxyl group-5,6,7,8-tetrahydrochysene pyrrole Azoles also [5,1-b] quinazoline-3-formonitrile HCN (20mg, 21% productivity).¹H NMR(300MHz,CDCl₃)δ8.25(s,1H),4.44 (s, 3H), 3.02 (t, J=6.3Hz, 2H), 2.80 (t, J=6.3Hz, 2H), 1.89 (m, 4H)；m/z(ESI)229[M+H]⁺。

By the method similar with embodiment 445, use suitable parent material to prepare and separate 6-ethyl-7-methoxy Base-5-methylpyrazole also [1,5-a] pyrimidine-3-formonitrile HCN.

Embodiment 446

The synthesis of 9-(2-hydroxyl-oxethyl)-5,6,7,8-tetrahydro-pyrazole also [5,1-b] quinazoline-3-formonitrile HCN

9-chloro-5,6,7,8-tetrahydro-pyrazoles also [5,1-b] quinazoline-3-formonitrile HCN (100mg, 0.43mmol), Et will be contained₃N (0.7mL) ethane-1,2-glycol (2mL) mixture is stirred at room temperature overnight.Reactant EtOAc (2.0mL) is diluted. Add hexane (2mL), thus cause product to precipitate.By product filter, with EtOAc washing thus obtain required white solid Compound 9-(2-hydroxyl-oxethyl)-5,6,7,8-tetrahydro-pyrazoles also [5,1-b] quinazoline-3-formonitrile HCN (2.0mg, 2% productivity) 。¹H NMR(300MHz,CDCl₃) δ 8.69 (s, 1H), 4.94 (t, J=5.1Hz, 1H), 4.79 (t, J=4.5Hz, 2H), 3.73 (m, 2H), 2.94 (t, J=5.7Hz, 2H), 2.82 (t, J=6.3Hz, 2H), 1.83 (m, 4H)；m/z(ESI)259[M+H]⁺。

Embodiment 447

The synthesis of 9-(2-methoxy ethoxy)-5,6,7,8-tetrahydro-pyrazole also [5,1-b] quinazoline-3-formonitrile HCN

9-chloro-5,6,7,8-tetrahydro-pyrazoles also [5,1-b] quinazoline-3-formonitrile HCN (100mg, 0.43mmol), Et will be contained₃N (0.7mL) 2-methyl cellosolve (2mL) mixture is stirred overnight at 70 DEG C.Remove solvent under vacuo, and by preparation Type thin layer chromatography crude product thus obtain required compound as white solid 9-(2-methoxy ethoxy)-5,6,7, 8-tetrahydro-pyrazole also [5,1-b] quinazoline-3-formonitrile HCN (10.0mg, 9% productivity).¹H NMR(300MHz,CDCl₃)δ8.24(s, 1H), 4.92 (m, 2H), 3.75 (m, 2H), 3.37 (s, 3H), 3.03 (t, J=6.0Hz, 2H), 2.84 (t, J=6.0Hz, 2H), 1.91(m,4H)；m/z(ESI)273[M+H]⁺。

Embodiment 448

The synthesis of 3-cyano group-6-ethyl-N-methyl-7-oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-5-Methanamide

The synthesis of 3-cyano group-6-ethyl-7-oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-5-carboxylic acid

To containing 3-cyano group-6-ethyl-7-oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-5-carboxylic acid's ethyl ester at 0 DEG C The EtOH (50mL) of (500mg, 1.92mmol) and H₂O (5mL) solution is dividedly in some parts LiOH (230mg, 9.6mmol).Will be anti- Mixture is answered to be stirred at room temperature 2 hours.Remove under vacuo after EtOH, add water (5mL) and mixture is filtered thus produce 3-cyano group-6-ethyl-7-oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-5-carboxylic acid of raw pale solid (380mg, 89%).¹H NMR (300MHz, DMSO-d6) δ 8.41 (s, 1H), 2.67 (q, J=6.9Hz, 2H), 1.09 (t, J=6.9Hz, 3H)。

The synthesis of 3-cyano group-6-ethyl-N-methyl-7-oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-5-Methanamide

To containing 3-cyano group-6-ethyl-7-oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-5-carboxylic acid (50mg, 0.21mmol), methylamine hydrochloride (15mg, 0.21mmol), PyBOP (105.20mg, 0.21mmol) and HOBT (41.85mg, DMF (2mL) solution 0.31mmol) adds DIEA (129mg, 1mmol).At room temperature reactant mixture is stirred overnight. By mixture CH₂Cl₂Dilute and by column chromatography eluting thus produce the 3-cyano group-6-ethyl-N-first of pale solid Base-7-oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-5-Methanamide (16mg, 31%).¹HNMR(300MHz,CD₃OD)δ 8.16 (s, 1H), 2.95 (s, 3H), 2.79 (q, J=7.5Hz, 2H), 1.20 (t, J=7.5Hz, 3H)；m/z(ESI)246[M+ H]⁺。

By the method similar with above-described embodiment 448, use ethylamine hydrochloride as reagent, prepare and separate 3-cyano group- N, 6-diethyl-7-oxo-4,7-pyrazoline [1,5-a] pyrimidine-5-formonitrile HCN.

Embodiment 449

The synthesis of 4-benzyl-9-oxo-4,5,6,7,8,9-hexahydro pyrazolo [5,1-b] quinazoline-3-formonitrile HCN

To containing 9-oxo-4,5,6,7,8,9-hexahydro pyrazolo [5,1-b] quinazolines-3-formonitrile HCN (50mg, 0.23mmol) DMF (1mL) solution in add potassium carbonate (63mg, 0.46mmol) and sodium iodide (5mg, 3mmol), be subsequently added into benzyl bromide a-bromotoluene (43mg, 0.25mmol).Mixture is stirred at room temperature overnight, then dilutes with water (10mL) and with EtOAc (5mL X 3) Extraction.The organic layer of merging is dried and is concentrated to dryness.By silica gel thick layer chromatography purification residue thus obtain 4-benzyl Base-9-oxo-4,5,6,7,8,9-hexahydro pyrazolo [5,1-b] quinazolines-3-formonitrile HCN (25mg, 35%).¹H NMR (300MHz,CDCl₃) δ 8.03 (s, 1H), 7.38 (m, 3H), 7.04 (d, J=5.6Hz, 2H), 5.56 (s, 2H), 2.68 (m, 4H),1.79(m,4H)；m/z(ESI)305[M+H]⁺。

Embodiment 450

The synthesis of 9-oxo-4-phenyl-4,5,6,7,8,9-hexahydro pyrazolo [5,1-b] quinazoline-3-formonitrile HCN

To containing 9-oxo-4,5,6,7,8,9-hexahydro pyrazolo [5,1-b] quinazolines-3-formonitrile HCN (645mg, 3mmol) CH₂Cl₂(20mL) solution adds Cu (OAc)₂, 4A molecular sieve, Et₃N (607mg, 6mmol), and it is subsequently added pyridine (474mg, 6mmol), by solution at O₂Lower stirring 2 days.NH is added in mixture₃H₂O is also regulated to PH > 8.After filtration, Solution is concentrated and by column chromatography eluting thus obtain the 9-oxo-4-phenyl-4,5,6,7,8,9-hexahydro of white solid Pyrazolo [5,1-b] quinazoline-3-formonitrile HCN (60mg, 10%).¹H NMR(300MHz,CD₃Cl)δ7.99(s,1H),7.52- 7.36(5H),2.81(m,2H),2.52(m,2H),1.80(m,4H)；m/z(ESI)291[M+H]⁺。

Embodiment 451

6-ethyl-5-(hydroxymethyl)-2-methyl-7-oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN Synthesis

At-78 DEG C, to the ethyl-5-containing 6-(methoxy)-2-methyl-7-oxo-4,7-dihydro-pyrazolo [1,5- A] CH of pyrimidine-3-formonitrile HCN (50mg, 0.2mmol)₂Cl₂(20mL) solution is added dropwise over BCl₃(1mL, 1mmol), by mixture At-78 DEG C, continue stirring 2 hours, the most at room temperature keep 16 hours.Go out mixture with shrend, and use CH₂Cl₂(20mL X 3) washing aqueous phase.After removing water, use CH₂Cl₂/ MeOH (50mL, V/V=20/1) debris also filters.Solution is concentrated And by column chromatography eluting thus obtain 6-ethyl-5-(the hydroxymethyl)-2-methyl-7-oxo-4,7-of pale solid Dihydro-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN (10mg, 23% productivity).¹H NMR(300MHz,CD₃OD)δ4.71(s,2H), 2.61 (m, 2H), 2.49 (s, 3H), 1.56 (t, J=7.2Hz, 3H)；m/z(ESI)233[M+H]⁺。

By the method similar with above-described embodiment 451, use suitable parent material to prepare and separate the chemical combination in table 5 Thing.

Table 5.

Embodiment 452

The synthesis of 6-ethyl-5-oxo-5,7,8,9-tetrahydro-pyrazole also [1,5-a] pyrrolo-[1,2-c] pyrimidine-1-formonitrile HCN

At 0 DEG C, to containing 6-ethyl-4,7-dihydro-5-(3-hydroxypropyl)-7-oxo pyrazoles also [1,5-a] pyrimidine-3- THF (10mL) solution of formonitrile HCN (12mg, 0.05mmol) adds DIAD (10mg, 0.06mmol) and PPh₃(16mg, 0.06mmol).Mixture is made to return to room temperature and be stirred overnight.By mixture be evaporated in vacuo, by column chromatography purification thus To 6-ethyl-5-oxo-5,7,8,9-tetrahydro-pyrazoles also [1,5-a] pyrrolo-[1,2-c] pyrimidine-1-formonitrile HCN (5mg, 43.8%).¹H NMR(300MHz,CD₃OD) δ 8.24 (s, 1H), 4.55 (t, J=7.5Hz, 2H), 3.23 (t, J=7.8Hz, 2H), 2.60 (q, J=7.5Hz, 2H), 2.47 (m, 2H), 1.18 (t, J=7.5Hz, 3H)；m/z(ESI)229[M+H]⁺。

Embodiment 453

The synthesis of 6-ethyl-5-formoxyl-7-oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN

At-78 DEG C, to the CH containing DMSO (780mg, 5mmol)₂Cl₂(50mL) solution is added dropwise over oxalyl chloride (127mg, 5mmol), then proceedes to stir 30 minutes.It is added dropwise over the ethyl-5-containing 6-(hydroxymethyl)-7-oxo-4,7-two The CH of hydrogen pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN (110mg, 0.5mmol)₂Cl₂(5mL).After stirring one hour, it is added dropwise over Et₃N (1.5g, 15mmol) also returns to ambient temperature.Mixture shrend is gone out, is used CH₂Cl₂(10mL X 3) extracts, merging Organic layer is through anhydrous Na₂SO₄It is dried and evaporates.Crude product is by column chromatography purification thus obtains the 6-ethyl-5-first of yellow solid Acyl group-7-oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN (50mg, 50%).¹H NMR(300MHz,CD₃Cl)δ 10.12 (s, 1H), 8.32 (s, 1H), 3.04 (q, J=7.2Hz, 2H), 1.23 (t, J=7.2Hz, 3H)；m/z(ESI)217[M+ H]⁺。

Embodiment 454

The synthesis of 6-ethyl-5-(1-hydroxyethyl)-7-oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN

At-60 DEG C, to containing 6-ethyl-5-formoxyl-7-oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN THF (10mL) solution of (50mg, 0.23mmol) is added dropwise over CH₃MgBr (0.7mL, 0.68mmol), and it is little to continue to stir 1 Time.The saturated NH of mixture₄Cl cancellation, and use CH₂Cl₂(20mL X 5) extracts.The organic layer merged is through anhydrous Na₂SO₄It is dried And evaporate.Crude product is by column chromatography purification thus obtains 6-ethyl-5-(1-hydroxyethyl)-7-oxo-4 of white solid, 7-dihydro-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN (5mg, 15%).¹H NMR(300MHz,CD₃OD)δ8.29(s,1H),5.22 (m, 1H), 2.65 (m, 2H), 1.59 (d, J=6.6Hz, 3H), 1.24 (t, J=7.5Hz, 3H)；m/z 233[M+H]⁺。

Embodiment 455

The synthesis of 9-oxo-4,9-dihydro-pyrazolo [5,1-b] quinazoline-3-formonitrile HCN

The synthesis of 2-acetaminobenzoic acid

The Ac of ortho-aminobenzoic acid (100g, 0.73mol) will be contained₂O (1000mL) heats 2 hours at 100 DEG C.Vacuum is steamed Send out Ac₂O and residue hexane wash thus obtain product as off-white solid 2-acetaminobenzoic acid (130g, 100%).¹H NMR(300MHz,CDCl₃)δ8.19(m,1H),7.79(m,1H),7.54(m,2H),2.48(s,3H)。

The synthesis of 3-amino-2-methyl quinazoline-4 (3H)-one

By 2-acetaminobenzoic acid (6.0g, 33.5mmol) and NH₂NH₂.H₂The mixture of O (5.9g, 100mmol) exists Stir 10 minutes at 0 DEG C and be heated to reflux 30 minutes.Remove after solvent, residu washed with ethanol thus obtain pale solid 3-amino-2-methyl quinazoline-4 (3H)-one (1g, 12.5%).¹H NMR(300MHz,CD₃OD)δ8.24(m,1H),7.75 (m,2H),7.46(m,1H),2.72(s,3H)。

The synthesis of 9-oxo-4,9-dihydro-pyrazolo [5,1-b] quinazoline-3-formaldehyde

According to Pandit, R.S.；Seshadri,S.Vilsmeier-Haack Reaction.Indian.J.Chem.1973,11 (6), 532-537 carry out Vilsmeier-Haack reaction.At 0 DEG C, Xiang Han POCl₃In DMF (5mL) solution of (2.7mL, 29mmol) add containing 3-amino-2-methyl quinazoline-4 (3H)-one (1.0g, DMF (10mL) 5.7mmol).Then mixture heated 5 hours at 70 DEG C and pour in trash ice.At 0 DEG C, by gained Butyrous solution NaHCO₃Alkalization, to pH=8, now isolates glassy yellow crystalline compounds.Crystallization is filtered, washed with water. Solid it is dissolved in solution of potassium carbonate (10%, 10mL) and at 60 DEG C, warms half an hour, now can obtain transparent yellow solution. Described solution HCl (1N) is neutralized to pH=5, and filters thus obtain 9-oxo-4 of pale solid, 9-pyrazoline And [5,1-b] quinazoline-3-formaldehyde (800mg, 82.5%).¹H NMR(300MHz,DMSO-d6)δ9.90(s,1H),8.44 (s,1H),8.24(m,1H),7.86(m,2H),7.42(m,1H).

The synthesis of 9-oxo-4,9-dihydro-pyrazolo [5,1-b] quinazoline-3-formaldoxime

By 9-oxo-4,9-dihydro-pyrazolo [5,1-b] quinazoline-3-formaldehyde (800mg, 3.75mmol) and oxammonium hydrochloride. (250mg, 3.6mmol) is dissolved in EtOH (50mL), and refluxes 3 hours.Remove solvent under vacuo thus obtain pale solid Crude product 9-oxo-4,9-dihydro-pyrazolo [5,1-b] quinazoline-3-formaldoxime (700mg, 82%).¹H NMR (300MHz,DMSO-d6)δ12.48(s,1H),11.35(s,1H),8.57(s,1H),8.21(m,1H),7.82(m,1H), 7.52(m,1H),7.34(m,1H)。

The synthesis of 9-oxo-4,9-dihydro-pyrazolo [5,1-b] quinazoline-3-formonitrile HCN

To containing 9-oxo-4,9-dihydro-pyrazolo [5,1-b] quinazoline-3-formaldoxime (600mg, 2.63mmol) anhydrous CHCl₃(10mL) solution adds phosphorus oxychloride (0.5mL, 5.5mmol), and mixture is refluxed 2 hours.Remove CH₃After Cl, Add ice cooling water, be subsequently added into sodium bicarbonate regulation pH and be about 8.Precipitate is filtered, washes with water thus obtain canescence 9-oxo-4 of solid, 9-dihydro-pyrazolo [5,1-b] quinazoline-3-formonitrile HCN (200mg, 30%).¹H NMR(300MHz, DMSO-d6) δ 13.33 (s, 1H), 8.43 (s, 1H), 8.23 (d, J=8.1Hz, 1H), 7.86 (dd, J=8.4Hz, 6.9Hz, 1H), 7.58 (d, J=8.1Hz, 1H), 7.41 (dd, J=8.1Hz, 7.2Hz, 1H)；m/z(ESI)211[M+H]⁺。

Embodiment 456

The synthesis of 3-Ethyl-2-Methyl-4-oxo-3,4-dihydro-pyrazolo [1,5-a] [1,3,5] triazine-8-formonitrile HCN

(E) synthesis of-N-4-cyano group-1H-pyrazoles-5-base ethyl acetimidate

It is similar to the chemical method described in US 4,892,576.To contain 5-amino-1H-pyrazoles-4-formonitrile HCN (1.1g, 10mmol), MeCN (74mL) solution of 1,1,1-triethoxy ethane (2g, 12mmol) and AcOH (3) refluxes 16 hours.Will Gained mixture is cooled to room temperature, vaporising under vacuum.By column chromatography purification residue thus obtain (E)-N-4-cyano group- 1H-pyrazoles-5-base ethyl acetimidate (400mg, 22%).¹H NMR(300MHz,CDCl₃)δ7.80(s,1H),4.33(q,J =7.2Hz, 2H), 2.10 (s, 3H), 1.38 (t, J=7.2Hz, 3H).

The synthesis of 3-Ethyl-2-Methyl-4-oxo-3,4-dihydro-pyrazolo [1,5-a] [1,3,5] triazine-8-formonitrile HCN

At 0 DEG C, to the nothing of the cyano group-1H-pyrazoles-5-base ethyl acetimidate Han (E)-N-4-(100mg, 0.56mmol) Water THF (5mL) solution adds TEA (57mg, 0.56mmol) and isocyanide acyl ethane (50mg, 0.7mmol).Mixture is warmed To ambient temperature and stir 18 hours.Under reduced pressure remove solvent, and purify residue by column chromatography thus obtain 3-ethyl-2- Methyl-4-oxo-3,4-dihydro-pyrazolo [1,5-a] [1,3,5] triazine-8-formonitrile HCN (10mg, 8.8% productivity).¹H NMR (300MHz,CD₃OD) δ 8.32 (s, 1H), 4.23 (q, J=7.2Hz, 2H), 2.73 (s, 3H), 1.42 (t, J=7.2Hz, 3H)； m/z(ESI)204[M+H]⁺。

Embodiment 457

The conjunction of 6-ethyl-5-((methylamino) methyl)-7-oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN Become

The synthesis of 5-(bromomethyl)-6-ethyl-7-oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN

At ambient temperature, to the ethyl-5-containing 6-(hydroxymethyl)-7-oxo-4,7-dihydro-pyrazolo [1,5-a] is phonetic Pyridine-3-formonitrile HCN (50mg, 0.228mmol) and PPh₃The CH of (120mg, 0.456mmol)₂Cl₂(10mL) solution adds CBr₄ (152mg, 0.456mmol).Reactant mixture is stirred 16 hours.Crude product is concentrated and passes through column chromatography purification thus obtain 5-(bromomethyl)-6-ethyl-7-oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN (30mg, 50%).m/z(ESI) 281/283[M+H]⁺。

The conjunction of 6-ethyl-5-((methylamino) methyl)-7-oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN Become

To containing 5-(bromomethyl)-6-ethyl-7-oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN (30mg, 5mL DMF solution 0.11mmol) adds Et₃N (22mg, 0.22mmol) and methylamine hydrochloride (15mg, 0.22mmol).At ring At a temperature of border, stir the mixture for 16h.Crude product is concentrated and passes through column chromatography purification thus obtain 6-ethyl-5-((methyl Amino) amino)-7-oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN (6mg, 20%).¹HNMR(300MHz, CD₃OD) δ 8.18 (s, 1H), 4.34 (s, 2H), 2.89 (s, 3H), 2.66 (q, J=7.5Hz, 2H), 1.20 (t, J=7.2Hz, 3H)；m/z(ESI)232[M+H]⁺。

Embodiment 458

Measure test compound to the GASC1 hepatic Microsomal Aniline Hydroxylase on H3 lysine 9 trimethyl peptide (H3K9me3) Inhibitory action

GASC1 demethylation measures

The restructuring GASC1 (N 350aa) of 6xHis labelling is to be purified to close to homogeneity by e. coli bl21 (DE3).Piptonychia Glycosylation reaction buffer comprises: 50mM TrisCl pH 7.5,0.01%Triton X-100,5% glycerol, 1mM ascorbic acid Salt (Cat#A4034, Sigma Aldrich), 5 μMs of α-ketoglutaric acid (#K2010, Sigma Aldrich) and 20 μMs of Fe₂ (NH₄)₂(SO₄)₂(Cat#F1543, Sigma Aldrich).In 25 μ L demethylation reaction systems, 400nM is recombinated GASC1 and 20 μMs of H3K9me3 peptides (1-21aa) and compound incubation 10 minutes, be subsequently adding α-ketoglutaric acid and Fe₂(NH₄)₂ (SO₄)₂Start reaction.The most at room temperature being hatched by all reactants 45 minutes, being subsequently adding 25 μ l 1N HCl, to carry out cancellation anti- Should.After termination, plate is sealed and-80 DEG C of freezings, and transport (on dry ice) to BioTrove Inc. (Woburn, MA) It is analyzed.

High flux mass spectrum (HT-MS) is analyzed

Responded the RapidFire developed by BioTrove Inc^TMHT-MS platform reads, and the most detailed Carefully describe method (Assay and Drug Development Technologies, 2004；2(4):373-381).Letter and Yan Zhi, uses the RapidFire coupled with tri-times of quadruple mass-spectrometers of Sciex API4000 at BioTrove^TMSystem is thawed also Analysis plates immediately.Sample is transferred directly to from plate clean box (BioTrove post A), to use 0.1% formic acid with washing in 3 seconds Circulation removes non-volatile mensuration composition.Use 80% acetonitrile, 0.1% formic acid, by peptide substrates and demethylated product co-elute To mass spectrograph.The signal both of substrate and product with its+5 charged species read, and by [H3K9me2 reading]/ [H3K9me2 reading+H3K9me3 reading] measures the substrate conversion to product.

Embodiment 459

Table 6 shows the activity of the compound of the selection of the present invention in GASC1 suppression measures.The numbering of compound and table In 1, the numbering of compound is corresponding.The compound of the activity with named " A " provides IC₅₀≤1μM；There is named " B " The compound of activity provides IC₅₀1-10μM；The compound of the activity with named " C " provides IC₅₀10-50μM；And have The compound of the activity of named " D " provides IC₅₀≥50μM。

Table 6.GASC1 suppresses data

Compound number	GASC1 suppresses
		I-1	D
I-2	D
		I-3	B
I-4	A
		I-5	B
I-6	D
		I-12	C
I-13	D
		I-14	D
I-15	B
		I-16	B
I-17	A
		I-18	D
I-19	D
		I-20	B
I-21	A
		I-22	B
I-23	B
		I-24	B
I-25	A
		I-26	B
I-27	D
		I-28	D
I-29	D
		I-30	B
I-31	B

Compound number	GASC1 suppresses
		I-32	B
I-33	B
		I-34	A
I-35	B
		I-36	D
I-37	D
		I-38	A
I-39	B
		I-40	B
I-41	A
		I-42	A
I-43	B
		I-44	A
I-45	A
		I-46	A
I-47	A
		I-48	B
I-49	B
		I-50	B
I-51	A
		I-52	B
I-53	B
		I-54	B
I-55	B

Embodiment 460

Measure test compound to JARID1A and the PLU-1 piptonychia on H3 lysine 4 trimethyl peptide (H3K9me3) The inhibitory action of base enzymatic activity

JARID1A/PLU1 demethylase measures

Total length restructuring JARID1A and the PLU1 albumen of FLAG labelling is to be purified to close to homogeneity by Sf9 insect cell.Piptonychia Glycosylation reaction buffer comprises: 50 mM TrisCl pH 7.5,0.01%Triton X-100,0.005%BSA, 1 mM are anti-bad Hematic acid salt (Cat#A4034, Sigma Aldrich), 1.7 μMs of α-ketoglutaric acid (#K2010, Sigma Aldrich) and 20 μMs Fe₂(NH₄)₂(SO₄)₂(Cat#F1543, Sigma Aldrich).In 25 μ L demethylation reaction systems, 20nM is recombinated JARID1A or PLU1 albumen and 4 μMs of H3K9me3 peptides (1-21aa) (described peptide can be biotinylated or unlabelled) with change Compound is hatched 10 minutes, is subsequently adding α-ketoglutaric acid and Fe₂(NH₄)₂(SO₄)₂Start reaction.By all reactants all in room Hatch under temperature 45 minutes, be subsequently adding 25 μ l 1N HCl and carry out cancellation reaction.After termination, plate is sealed and at-80 DEG C freezing with For analyzing.

High flux mass spectrum (HT-MS) is analyzed

Responded the RapidFireTM HT-MS platform all developed by BioCius Inc to read, and obtained Detailed description (Assay and Drug Development Technologies, 2004；2(4):373-381).In short It, use the RapidFire coupled with tri-times of quadruple mass-spectrometers of Sciex API4000^TMSystem is thawed and is existed side by side i.e. analysis plates.By sample Product are transferred directly on clean box (BioCius post A) from plate, to use 0.1% formic acid to remove non-volatile with 3 seconds cycles of washing Property measure composition.Use 80% acetonitrile, 0.1% formic acid, by peptide substrates and demethylated product co-elute to mass spectrograph.Substrate With the signal of product all to read at its+5 charged species, and by [H3K4me2 reading]/[H3K4me2 reading+H3K4me3 Reading] measure the substrate conversion to product.

Embodiment 461

Table 7 shows the activity of the compound of the selection of the present invention in JARID1A and PLU-1 suppression measures.Compound Numbering corresponding with the numbering of compound in table 1.The compound of the activity with named " A " provides IC₅₀≤1μM；Have The compound of the activity of named " B " provides IC₅₀1-10μM；The compound of the activity with named " C " provides IC₅₀10-50 μM；And the compound with the activity of named " D " provides IC₅≥50μM。

Table 7.JARID1A and PLU-1 suppresses data

Compound number	JARID1A	PLU-1
			I-4	B	B
I-21	A	A
			I-23	A	A
I-25	A	A
			I-29	B	B
I-30	A	A
			I-49	A	B

Although we have described many embodiment of the present invention, but it is clear that our basic enforcement can be changed Example is to provide other embodiments of the Compounds and methods for using the present invention.It is therefore understood that the scope of the present invention by Appending claims limits rather than is limited by the specific embodiments representated by embodiment.

Embodiment 462

Measure the test compound inhibitory action to KDM5A hepatic Microsomal Aniline Hydroxylase

KDM5A demethylase measures (MassSpec mensuration-A)

The KDM5A albumen of total length restructuring Flag labelling is by purification in Sf9 insect cell.Demethylation reaction buffer bag Contain: 50mM TrisCl pH 7.4,0.01%Triton X-100,0.025mg BSA, 1mM Ascorbate (Cat#A4034, Sigma Aldrich), 2mM TCEP (Cat#D9779, Sigma Aldrich), 2.0 μMs of α-ketoglutaric acid (#K2010, Sigma Aldrich) and 50 μMs of Fe₂(NH₄)₂(SO₄)₂(Cat#F1543, Sigma Aldrich).In 25 μ L demethylation reaction systems In, the KDM5A that recombinated by 20nM is hatched 10 minutes with compound in above-mentioned buffer, is subsequently adding 2.0 α-ketoglutaric acid (# K2010, Sigma Aldrich), 4.0 μMs of biotinylations H3K9me1 peptide (1-21aa) and Fe₂(NH₄)₂(SO₄)₂Start reaction. (all reagent concentrations are final reagent concentration.) reactant is at room temperature hatched 30 minutes, it is subsequently adding isopyknic 1% Formic acid carrys out cancellation reaction.After termination, plate is sealed and freezing for analysis at-80 DEG C.

KDM5A demethylase measures (TR-FRET mensuration-B)

The KDM5A albumen of total length restructuring Flag labelling is by purification in Sf9 insect cell.Demethylation reaction buffer bag Contain: 50mM TrisCl pH 7.4,0.01%Triton X-100,0.025mg/mL BSA, 1mM Ascorbate, 2mM TCEP, 3.0 μMs of α-ketoglutaric acid and 50 μMs of Fe₂(NH₄)₂(SO₄)₂.In 10 μ L demethylation reaction systems, 2nM is recombinated KDM5A and compound are at the above-mentioned buffer (V in 384 hole Proxi plates (Perkin Elmer Corp.)_tHatch in 5uL) 15 minutes, it is subsequently adding 0.1 μM of biotinylated H3K9me1 peptide (1-21aa, New England Peptide, V_t5uL) come Start reaction (V_t10uL).(concentration of all proteins/reagent is ultimate density.) reactant at room temperature hatched 25 Minute, it is subsequently adding 5uL detectable and (in above-mentioned buffer, adds 0.3mM EDTA, 150mM NaCl, 150nM SA- (TR-FRET reagent, both of which is purchased from the buffer of SurelightAPC and 1.5nM Eu (W1024)-K3K4Me1/2 antibody Perkin-Elmer) cancellation reaction) is carried out.After hatching one hour, equipped with lasing light emitter and the Perkin-of suitable optical filter Mensuration is read on Elmer Envision.Use standard dose-reaction equation and relative to maximum (unrestraint) and minimum (nothing Enzyme or cancellation enzyme) comparison calculating IC₅₀s。

KDM5A demethylase measures (TR-FRET mensuration-C)

The KDM5A albumen of total length restructuring Flag labelling is by purification in Sf9 insect cell.Demethylation reaction buffer bag Contain: 50mM HEPES pH 7.0,0.01%Triton X-100,0.5mM Ascorbate, 2mM DTT, 1 μM of α-ketoglutaric acid With 100 μMs of Fe₂(NH4)₂(SO₄)₂.In 10 μ L demethylation reaction systems, the KDM5A that recombinated by 2nM joins in 384 holes Above-mentioned buffer (the V of Proxi plate (Perkin Elmer Corp.) inclusion compounds_tIn 5uL), it is subsequently adding 0.1 μM of biology Elementization H3K9me1 peptide (1-21aa, New England Peptide, V_t5uL) start reaction (V_t10uL).(all albumen The concentration of matter/reagent is ultimate density.) reactant is at room temperature hatched 30 minutes, it is subsequently adding 5uL stop buffer (3mM EDTA, 50mM TrisCl pH 7.5,0.01%Triton X-100,0.01mg/mL BSA), is subsequently added into 5uL inspection Test agent is (to above-mentioned without adding 200nM SA-XL665 (CisBio) and 2nM Eu (W1024)-anti-in the buffer of EDTA The buffer of H3K4Me1-2 antibody (PerkinElmer)) carry out cancellation reaction.After hatching 30 minutes, equipped with suitable optical filter Perkin-Elmer Envision on read mensuration.Use standard dose-reaction equation and relative to maximum (unrestraint) IC is calculated with minimum (without enzyme or cancellation enzyme) comparison₅₀s。

Embodiment 463

KDM5 enzymatic determination program

Total length KDM5A enzyme is at internal representations purification.Biotin-H3K4me3 peptide is purchased from New England Biolabs. HTRF reagent (the H3K4me1-2 antibody containing Eu-labelling and Streptavidin-XL665) is purchased from Cis-Bio International.Envision multiple labeling plate reader (Perkin Elmer) reads plate.

HTRF measures mixture and comprises 2nM total length KDM5A enzyme, 100nM H3K4Me3 peptide substrates, 1uM 2-OG, 100uM Fe²⁺, 500uM Ascorbate, 50mM HEPES pH 7.0 buffer, 0.01%Triton-X 100,2mM DTT, 0.25% DMSO, final volume is 10uL.In the presence of the test compound of variable concentrations, at room temperature at black in 30 minutes Enzyme reaction is carried out in Proxiplate 384-Plus plate (Corning, Costar).At the end of enzyme reaction, add 5uL 1mM EDTA carrys out cancellation reaction, is subsequently adding detectable (5uL) thus obtains the Eu-labelling that ultimate density is 0.5nM H3K4me1-2 antibody and 50nM Streptavidin-XL665.Plate is at room temperature hatched 60 minutes, then at Envision flat board Reader reads.Reading is changed into % suppression, and by use four parameter curves (model 205 in XLFIT5, IDBS) the IC50 value of test compound is generated.

Embodiment 464

KDM5 raji cell assay Raji program

PC9 cell is seeded on 384 orifice plates (2000 cells/well) with test compound, and incubates at 37 DEG C Educate 120 hours.Use and measure H3K4Me3 mark grade purchased from the AlphaLISA reagent of Perkin Elmer.In brief, will Cell cracks 30 minutes on ice with 5 μ L histone lysis buffers.Then by adding 10 μ L histones extractions in each hole Take buffer to continue to carry out extraction battery albumen in 20 minutes.Between be sequentially added into 10 μ L acceptor bead and 10 μ L donor bead every other hour, then Mixture is hatched 30 minutes at 26 DEG C.Assay plate is read subsequently on Envision (Perkin Elmer).To each chemical combination Thing reruns twice.The hole that data standard turns to DMSO process as low-response and uses four parameter fittings to calculate EC₅₀’s。

Provide the data of compound from embodiment 1-432 in measuring described in embodiment 463 in the following table.

Provide the representative compound from the Formulas I-1 measured described in embodiment 463 to Formulas I-65 in the following table Data.

Although it have been described that many embodiments, but these embodiments can be changed to provide use described herein Other embodiments of Compounds and methods for.Therefore, the scope of the present invention be limited by the accompanying claims rather than by The detailed description of the invention that embodiment represents limits.

Claims (107)

1. a compound of formula I:

Or its pharmaceutically acceptable salt, wherein:

R¹For-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O) C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N (R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂、- C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；

Each R independently be hydrogen or the optionally substituted group selected from the following: C_1-6Aliphatic series, phenyl, 3-7 unit saturated or Part unsaturated carbocyclic, 8-10 unit dicyclo be saturated, part unsaturated or aromatic ring, has 1-3 independently selected from nitrogen, oxygen or sulfur Heteroatomic 5-6 unit monocycle hetero-aromatic ring, there is 1-2 the saturated or part of heteroatomic 4-7 unit independently selected from nitrogen, oxygen or sulfur Undersaturated heterocycle, there is 1-4 independently selected from the heteroatomic 7-10 unit dicyclo of nitrogen, oxygen or sulfur is saturated or part is unsaturated Heterocycle or there is 1-4 the heteroatomic 8-10 unit Bicyclic heteroaromatic rings independently selected from nitrogen, oxygen or sulfur；

Each R ' independently be-R ,-C (O) R ,-CO₂Shape together with R or two R ' on same nitrogen and the atom between them Become to have 1-2 the heteroatomic 4-7 unit heterocycle independently selected from nitrogen, oxygen and sulfur；

Ring A is

R²And R³Independently be-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C (O)SR、-C(O)C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N (R′)C(O)R、-N(R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R′))N(R′)₂,-C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R²And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 0-4 The unsaturated ring of 5-7 unit part of atom or aromatic condensed ring；

R^2′For-R ,-OR ,-SR ,-N (R ')₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O)C(O)R、-C(O) CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N(R′)C(O)N (R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂,-C=NN (R′)₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R^2′And R³Formed together with the atom between them and optionally substituted there is 1-4 independently selected from nitrogen, oxygen and sulfur Heteroatomic 5-7 unit part unsaturation or aromatic condensed ring；

X is-N (R⁴)-,-O-or-S-；

R⁴For-R ,-C (O) R ,-CO₂R or-S (O)₂R；Or:

R⁴And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 1-4 The 5-7 unit of atom is saturated, part is unsaturated or aromatic condensed ring；

R⁵For R ,-C (O) R ,-CO₂R、-C(O)N(R′)₂,-C (O) C (O) R or-C (O) CH₂C(O)R；Or:

R⁵And R²Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 1-4 The unsaturated ring of 5-7 unit part of atom or aromatic condensed ring；And

R⁶For-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O) C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N (R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂、- C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R⁶And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 0-4 The unsaturated ring of 5-7 unit part of atom or aromatic condensed ring；

Condition be described compound be not following any one:

And condition be described compound be not the compound of formula (II):

Wherein:

Work as R²For ethoxy carbonyl and R³During for H, R¹For 3-(methylamino) propyl group；

Work as R²For H and R³It is 2, during 3-dihydro-Isosorbide-5-Nitrae-benzo dioxine-6-base, R¹For H；

Work as R²For H and R³During for 4-chlorphenyl, R¹For methoxyl group；

Work as R²For H and R³During for 4-chlorphenyl, R¹For hydroxyl；

Work as R²For ethyl, ethoxy carbonyl methyl, 2-hydroxypropyl, 2-(acyloxy) propyl group, 2-(acyloxy) ethyl, 2-(2- (N-Benzyoxycarbonylamino) propionyloxy) propyl group, 2-chloropropyl, 1-(ethoxy carbonyl) ethyl, ethoxy carbonyl methyl, 1- (carbonyl) ethyl, 1-(1-(dion e) ethoxy carbonyl) ethyl, 2-hydroxyl-1-Methylethyl, 2-ethoxy or 4-(trifluoromethylthio) benzyl and R³During for methyl, R¹For H；

Work as R²For H and R³For phenyl, tetrahydropyran-4-base methyl, chloromethyl, methoxycarbonyl, ethoxy carbonyl methyl, benzyl When base or 1-(2-fluorophenyl) cyclopropyl, R¹For H；

Work as R²For H, 4-benzyloxy-phenyl, 3,4-dihydro-6,7-dimethyl-3-oxo-2-quinoxalinyl or indol-3-yl, 3-pyrrole Oxazolyl, ethoxy carbonyl, cyano group, 3,4-dihydro-3-oxo-2-quinoxalinyl or carbonyl and R³During for H, R¹For H；

Work as R²For H and R³During for trifluoromethyl, R¹For 3-amino piperidine subbase；

Work as R²For H and R³During for methyl, R¹For H, methyl, phenyl, N-(4-fluorophenyl) amino, N-phenyl amino, N-benzyl ammonia Base, N-(3,5-Dimethoxyphenyl) amino, N-(3-methoxyphenyl) amino, N-(4-methoxyphenyl) amino, N-(3,4- Dimethoxyphenyl) amino, N-(4-aminomethyl phenyl) amino, N-(2-methoxyphenyl) amino, 4,5,6,7-tetrahydrochysene-1H-Yin Diindyl-2-base, N-(4-fluorophenyl) amino or N-(4-propyl group phenyl) amino；

Work as R²For H and R³During for isopropyl, R¹For phenyl amino；

Work as R²For H and R³During for phenyl, 2-fluorophenyl, 2-chlorphenyl or chloromethyl, R¹For N-(3,5-Dimethoxyphenyl) ammonia Base；

Work as R²For chlorine and R³During for methyl, R¹For N-(3,5-Dimethoxyphenyl) amino；

Work as R²For H and R³During for ethyl, R¹For methyl, N-(4-morphlinophenyl) amino, N-(3-methoxyl group-4-(2-morpholine For ethyoxyl) phenyl) amino, N-(3,5-Dimethoxyphenyl) amino or N-(4-propyl group phenyl) amino；

Work as R²For H and R³During for cyclopropyl, R¹For N-(3-methoxyl group-5-(2-morpholino ethyoxyl) phenyl) amino, N-(3, 5-Dimethoxyphenyl) amino, phenyl amino, N-(4-bromophenyl) amino or N-(4-morphlinophenyl) amino；

Work as R²For H and R³During for isopropyl, R¹For N-(3,5-Dimethoxyphenyl) amino；

Work as R²For methyl and R³During for methyl, R¹For N-(3,5-Dimethoxyphenyl) amino；

Work as R²For fluorine and R³During for methyl, R¹For N-(3,5-Dimethoxyphenyl) amino；

Work as R²For H and R³During for methoxy, R¹For N-(3,5-Dimethoxyphenyl) amino；

Work as R²For H and R³During for Methoxycarbonylmethyl, R¹For N-(3,5-Dimethoxyphenyl) amino；

Work as R²For H and R³During for propyl group, R¹For H, methyl or N-(3,5-Dimethoxyphenyl) amino；

Work as R²For benzyl and R³During for methyl, R¹For H, methyl or N-(3,5-Dimethoxyphenyl) amino；

Work as R²For benzyl and R³During for H, R¹For H or methyl；

Work as R²For H and R³During for phenyl, 2-pyridine radicals or N, N-dimethylaminomethyl, R¹For N-(3,5-dimethoxy benzene Base) amino；

Work as R²For 2-hydroxyethyl, 2-chloroethyl, 2-(acyloxy) ethyl and R³During for ethoxy carbonyl, R¹For H；

Work as R²For 2-hydroxyethyl and R³During for hydroxyl, R¹For H；

Work as R²For 2-(acyloxy) ethyl and R³During for benzyloxymethyl, R¹For H；

Work as R²For H and R³During for H, R¹For 2-pyrrole radicals；

Work as R²For 3,4-dihydro-6,7-dimethyl-3-oxo-2-quinoxalinyl and R³During for H, R¹For N-(4-ethoxybenzene Base) amino；

Work as R²For 2-(acyloxy) ethyl and R³During for methoxy, R¹For H；

Work as R²For cyano group and R³During for phenyl or 4-chlorphenyl, R¹For H；

Work as R²For 3,4-dihydro-3-oxo-2-quinoxalinyl and R³During for H, R¹For methyl；

Work as R²And R³When formation condenses benzo ring together, R¹For H；

Work as R²For 3-methoxy-benzyl and R³During for propyl group, R¹For H；

Work as R²For H, ethyl, ethoxy carbonyl methyl or 3-chlorobenzyl and R³During for methyl, R¹For methyl；

Work as R²For H and R³During for 3-chlorobenzyl, 5-(propyl group) isoxazole-3-base or 4-nitrobenzophenone, R¹For pyrrolidino；

Work as R²For H and R³During for Pentamethylene oxide .-2-base, R¹For morpholino；

Work as R²For benzoyl-amido and R³During for H, R¹For pyrrolidino；

Work as R²For H and R³During for 4-nitrobenzophenone, R¹For N-(4-methoxyphenyl) amino；

Work as R²For 2-(2,4 dichloro benzene formyloxy) ethyl, 2-(3-toluyl epoxide) ethyl, 2-(acetate) ethyl or 2-(cyclohexyl-carbonyl epoxide) ethyl and R³During for methyl, R¹For H；

Work as R²And R³When forming fused rings amyl group ring together, R¹For methyl；

Work as R²And R³When formation condenses cyclohexyl ring together, R¹For H；

Work as R²For H and R³During for ethoxy carbonyl methyl, R¹For methyl；

Work as R²For H and R³During for methyl or amino, R¹For phenyl；

Work as R²For chlorine and R³During for methyl, R¹For H；

R¹For methyl, R²For H, and R³For phenyl；

R¹For methyl, R²For 2-hydroxyethyl, and R³For methyl；Or

R¹For methyl mercapto, R²For H, and R³For phenyl；And

Condition be described compound be not following any one:

Compound the most according to claim 1, wherein said compound has a Formula II:

Or its pharmaceutically acceptable salt.

Compound the most according to claim 2, wherein R⁴For hydrogen.

Compound the most according to claim 1, wherein R¹For hydrogen.

Compound the most according to claim 1, wherein R¹For C_1-6Alkyl.

Compound the most according to claim 5, wherein R¹For methyl.

Compound the most according to claim 1, wherein R²For optionally substituted C_1-6Aliphatic series.

Compound the most according to claim 7, wherein R²For methyl, ethyl, propyl group, cyclopropyl, isopropyl, isobutyl group, alkynes Propyl group or pi-allyl.

Compound the most according to claim 7, wherein said C_1-6Aliphatic group is by-OCH₃Replace.

Compound the most according to claim 1, wherein R³For optionally substituted C_1-6Aliphatic series.

11. compound according to claim 10, wherein R³For methyl.

12. compounds according to claim 10, wherein said C_1-6Aliphatic group is by-OH or-OC_1-6Alkyl replaces.

13. compound according to claim 12, wherein R³For-CH₂OH、-CH₂CH₂OH、-CH₂CH₂CH₂OH、- CH₂OCH₂CH₃、-CH₂OCH₃、-CH₂CH₂CH₂OCH₃、-CH(OH)CH₃Or-CH₂CH₂OCH₃。

14. compounds according to claim 10, wherein said C_1-6Aliphatic group is by-NHC_1-6Alkyl or-NH (C_1-6Alkane Base)₂Replace.

15. compound according to claim 14, wherein R³For-CH₂NHCH₃。

16. compound according to claim 10, wherein R³For optionally substituted benzyl.

17. compound according to claim 10, wherein R³For one below:

18. compound according to claim 10, wherein R³For one below:

19. compound according to claim 10, wherein R³For-CF₃。

20. compound according to claim 1, wherein R³For-CO₂R or-C (O) N (R ')₂。

21. compound according to claim 20, wherein R³For-CO₂Et、-CO₂Bn、-CONHCH₃Or-CONHCH₂CH₃。

22. compound according to claim 1, wherein R³For having 1-3 the hetero atom independently selected from nitrogen, oxygen or sulfur 5-6 unit monocycle hetero-aromatic ring.

23. compound according to claim 1, wherein R²And R³The 5-6 unit condensed is formed together with the atom between them The unsaturated ring of part or aromatic carbocyclic.

24. compounds according to claim 2, wherein said compound has with one of following formula:

25. compound according to claim 1, wherein R²And R³Neither of which is hydrogen.

26. compounds according to claim 1, wherein said compound has with following formula:

Or its pharmaceutically acceptable salt.

27. compounds according to claim 26, wherein said compound has with following formula:

28. compounds according to claim 1, wherein said compound has a formula IV:

Wherein R⁵For optionally substituted C_1-6Aliphatic series.

29. compound according to claim 28, wherein R⁵For methyl.

30. compound according to claim 28, wherein R⁵For CH₂CH₂OCH₃。

31. compounds according to claim 1, wherein said compound has a Formula V:

32. 1 kinds of compounds selected from the group consisted of:

And pharmaceutically acceptable salt.

33. compounds as claimed in claim 1, it is formula (II) compound:

Or its salt, wherein:

R¹For H, C_1-6Alkyl, trifluoromethyl, 3-6 unit carbocylic radical, 6 yuan of aryl, 3-6 unit heterocyclic radical, 5-6 unit heteroaryl, halos Base ,-OR^f、-SR^f、-N(R^f)₂,-CN or-NO₂, wherein said alkyl, carbocylic radical, aryl, heteroaryl and heterocyclic radical by one or Multiple independently selected from oxo base, halogeno-group, C_1-3Alkoxyl and C_1-3The group of alkyl optionally replaces；

R²And R³It is each independently H, C_1-12Alkyl, C_2-12Thiazolinyl, C_2-12Alkynyl, carbocylic radical, aryl, heterocyclic radical, heteroaryl, halogen Dai Ji ,-OR^a、-SR^a、-N(R^a)₂、-CN、-NO₂、-C(O)R^a、-CO₂R^a、-C(O)N(R^a)₂、-C(O)SR^a、-C(O)C(O)R^a、- C(O)CH₂C(O)R^a、-C(S)N(R^a)₂、-C(S)OR^a、-S(O)R^a、-SO₂R^a、-SO₂N(R^a)₂,、-N(R^a)C(O)R^a、-N(R^a)C (O)N(R^a)₂,、-N(R^a)SO₂R^a、-N(R^a)SO₂N(R^a)₂、-N(R^a)N(R^a)₂、-N(R^a) C (=N (R^a))N(R^a)₂,-C (=N) N(R^a)₂,-C=NOR^a,-C (=N (R^a))N(R^a)₂、-OC(O)R^aOr-OC (O) N (R^a)₂, wherein R²And R³C_1-12Alkyl, C_2-12Thiazolinyl, C_2-12Alkynyl, carbocylic radical, aryl, heteroaryl and heterocyclic radical are independently of one another by one or more R^xGroup is optionally Replace, and wherein R²And R³It is not each H；Or R²And R³4,5,6,7 or 8 yuan of carbon are formed together with the atom being connected with them Ring group or aryl, described carbocylic radical or aryl are by one or more R^xGroup optionally replaces；

R⁴For H, C_1-12Alkyl, C_2-12Thiazolinyl, C_2-12Alkynyl, carbocylic radical, aryl, heteroaryl and heterocyclic radical, wherein C_1-12Alkyl, C_2-12Thiazolinyl, C_2-12Alkynyl, carbocylic radical, aryl, heteroaryl and heterocyclic radical each by one or more independently selected from oxo base, C_1-12Alkyl, C_1-12Haloalkyl, carbocylic radical, aryl, heterocyclic radical, heteroaryl, halogeno-group ,-CN ,-NO₂、-NR^mR^m、-OR^m、-C (=O) OR^mWith-OC (=O) R^mGroup optionally replace；Or R⁴And R³Heterocyclic radical is formed together with the atom being connected with them；

Each R^aIndependently selected from H, C_1-6Alkyl, C_2-6Thiazolinyl, C_2-6Alkynyl, carbocylic radical, aryl, heteroaryl and heterocyclic radical, its Middle C_1-6Alkyl, C_3-6Thiazolinyl, C_3-6Alkynyl, carbocylic radical, aryl, heteroaryl and heterocyclic radical are each by one or more R^xGroup is appointed Selection of land replaces；

Each R^fIndependently selected from H, C_1-3Alkyl, trifluoromethyl, 3-6 unit carbocylic radical, 6 yuan of aryl, 3-6 unit heterocyclic radical and 5-6 unit Heteroaryl, or two R^f3-6 unit heterocycle is formed with them together with the nitrogen that group is connected；

Each R^mIndependently selected from H, C_1-6Alkyl, C_2-6Thiazolinyl, C_2-6Alkynyl, C_1-6Haloalkyl, carbocylic radical, C_1-6Alkanoyl, benzene Base and benzyl, any of which C_1-6Alkyl, C_2-6Thiazolinyl, C_2-6Alkynyl, C_1-6Haloalkyl, carbocylic radical, C_1-6Alkanoyl, phenyl Or benzyl by one or more independently selected from halogeno-group ,-CN ,-NO₂、-NR^yR^zWith-OR^wGroup optionally replace；Or Two R^m3-6 unit heterocycle is formed with them together with the nitrogen that group is connected；

Each R^vIndependently be hydrogen, C_1-6Alkyl, C_2-6Thiazolinyl, C_2-6Alkynyl, carbocylic radical, aryl, heteroaryl and heterocyclic radical, wherein C_1-6Alkyl, C_2-6Thiazolinyl, C_2-6Alkynyl, carbocylic radical, aryl, heteroaryl and heterocyclic radical each by one or more independently selected from Oxo base, halogeno-group, amino, hydroxyl, aryl, carbocylic radical and C_1-6The group of alkyl optionally replaces, described C_1-6Alkyl quilt One or more groups independently selected from oxo base and halogeno-group optionally replace；Or two R^vThe nitrogen one being connected with them Rise and formed by one or more independently selected from oxo base, halogeno-group and C_1-3The optionally substituted heterocyclic radical of group of alkyl, institute State C_1-3Alkyl is optionally replaced by one or more groups independently selected from oxo base and halogeno-group；

Each R^wIndependently selected from H, C_1-4Alkyl, C_1-4Alkanoyl, phenyl, benzyl and phenethyl；

Each R^xIndependently selected from oxo base, C_1-6Alkyl, C_2-6Thiazolinyl, C_2-6Alkynyl, carbocylic radical, aryl, heteroaryl, heterocycle ,- F、-Cl、-Br、-I、-NO₂、-N(R^v)₂、-CN、-C(O)-N(R^v)₂、-S(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-O-R^v、-S- R^v、-O-C(O)-R^v、-O-C(O)-O-R^v、-C(O)-R^v、-C(O)-O-R^v、-S(O)-R^v、-S(O)₂-R^v、-O-C(O)-N (R^v)₂,、-N(R^v)-C(O)-OR^v、-N(R^v)-C(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-N(R^v)-C(O)-R^v、-N(R^v)-S (O)-R^v、-N(R^v)-S(O)₂-R^v、-N(R^v)-S(O)-N(R^v)₂And-N (R^v)-S(O)₂-N(R^v)₂, any of which C_1-6Alkane Base, C_2-6Thiazolinyl, C_2-6Alkynyl, carbocylic radical, aryl, heteroaryl, heterocycle by one or more independently selected from R^xa, oxo base, halogen Dai Ji ,-NO₂、-N(R^v)₂、-CN、-C(O)-N(R^v)₂、-S(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-O-R^v、-S-R^v、-O-C (O)-R^v、-C(O)-R^v、-C(O)-O-R^v、-S(O)-R^v、-S(O)₂-R^v、-C(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-N(R^v)-C (O)-R^v、-N(R^v)-C(O)-OR^v、-N(R^v)-S(O)-R^v、-N(R^v)-S(O)₂-R^vAnd C_1-6The group of alkyl optionally takes Generation, described C_1-6Alkyl is optionally replaced by one or more groups independently selected from oxo base and halogeno-group；

Each R^yAnd R^zIndependently selected from H, C_1-4Alkyl, C_1-4Alkanoyl, C_1-4Alkoxy carbonyl group, phenyl, benzyl and phenethyl, or R^yAnd R^zHeterocyclic radical is formed together with the nitrogen being connected with them；

Each R^xaIndependently selected from aryl, heteroaryl, heterocycle and carbocylic radical, any of which aryl, heteroaryl, heterocycle and carbocyclic ring By one or more independently selected from C_1-6Alkyl, C_2-6Thiazolinyl, C_2-6Alkynyl ,-F ,-Cl ,-Br ,-I ,-NO₂、-N(R^v)₂、-CN、 Carbocyclic ring, aryl ,-C (O)-N (R^v)₂、-S(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-O-R^v、-S-R^v、-O-C(O)-R^v、-O-C (O)-O-R^v、-C(O)-R^v、-C(O)-O-R^v、-S(O)-R^v、-S(O)₂-R^v、-O-C(O)-N(R^v)₂、-N(R^v)-C(O)-OR^v、- N(R^v)-C(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-N(R^v)-C(O)-R^v、-N(R^v)-S(O)-R^v、-N(R^v)-S(O)₂-R^vWith And-N (R^v)-S(O)-N(R^v)₂Group optionally replace, any of which C_1-6Alkyl, C_2-6Thiazolinyl and C_2-6Alkynyl is by one Or it is multiple independently selected from oxo base, halogeno-group ,-NO₂、-N(R^v)₂、-CN、-C(O)-N(R^v)₂、-S(O)-N(R^v)₂、-S(O)₂- N(R^v)₂、-O-R^v、-S-R^v、-O-C(O)-R^v、-C(O)-R^v、-C(O)-O-R^v、-S(O)-R^v、-S(O)₂-R^v、-C(O)-N (R^v)₂、-S(O)₂-N(R^v)₂、-N(R^v)-C(O)-R^v、-N(R^v)-S(O)-R^vAnd-N (R^v)-S(O)₂-R^vGroup optionally Replace.

34. compounds as claimed in claim 33, wherein R¹For H, C_1-6Alkyl, trifluoromethyl, 3-6 unit carbocylic radical, 6 yuan of virtues Base, 3-6 unit heterocyclic radical, 5-6 unit heteroaryl, halogeno-group ,-OR^f、-SR^f、-N(R^f)₂,-CN or-NO₂, wherein said alkyl, carbocyclic ring Base, aryl, heteroaryl and heterocyclic radical by one or more independently selected from oxo base, halogeno-group, C_1-3Alkoxyl and C_1-3Alkyl Group optionally replace.

35. compounds as claimed in claim 33, wherein R¹For H, methyl or ethyl.

36. compounds as claimed in claim 33, wherein R¹For H.

37. compound as according to any one of claim 33 to 36, wherein R²For H.

38. compound as according to any one of claim 33 to 36, wherein R²For C_1-12Alkyl, C_2-12Thiazolinyl, C_2-12Alkynyl, Carbocylic radical, aryl, heterocyclic radical, heteroaryl, halogeno-group ,-OR^a、-SR^a、-N(R^a)₂、-CN、-NO₂、-C(O)R^a、-CO₂R^a、-C(O) N(R^a)₂、-C(O)SR^a、-C(O)C(O)R^a、-C(O)CH₂C(O)R^a、-C(S)N(R^a)₂、-C(S)OR^a、-S(O)R^a、-SO₂R^a、- SO₂N(R^a)₂、-N(R^a)C(O)R^a、-N(R^a)C(O)N(R^a)₂、-N(R^a)SO₂R^a、-N(R^a)SO₂N(R^a)₂、-N(R^a)N(R^a)₂、-N (R^a) C (=N (R^a))N(R^a)₂,-C (=N) N (R^a)₂,-C=NOR^a,-C (=N (R^a))N(R^a)₂、-OC(O)R^aOr-OC (O) N (R^a)₂, wherein R²C_1-12Alkyl, C_2-12Thiazolinyl, C_2-12Alkynyl, carbocylic radical, aryl, heteroaryl and heterocyclic radical are independently of one another By one or more R^xGroup optionally replaces.

39. compound as according to any one of claim 33 to 36, wherein R²For H, C_1-6Alkyl, C_2-12Thiazolinyl, C_2-12Alkynes Base, carbocylic radical, aryl, heteroaryl, halogeno-group ,-CN ,-SR^a、-N(R^v)₂With-CO₂R^a, any of which C_1-6Alkyl, carbocylic radical With aryl by one or more independently selected from C_1-3Alkyl, carbocylic radical, halogeno-group ,-CN ,-N (R^v)-C(O)-R^vWith-O-R^v's Group optionally replaces.

40. compound as according to any one of claim 33 to 36, wherein R²For H, isopropyl, ethyl, the tert-butyl group, 2,2- Two fluoro ethyls, cyclobutyl, 2-propine-1-base, bromine, chlorine, 2-furyl, vinyl, phenyl, 2-chlorophenylsulfanyl, 2-fluoro ethyl, 2- Acrylic, 1-ethylene methacrylic cyclopropyl, 4-pyridine radicals, 2-butylene-1-base, iodine, 1-methyl-2-propine-1-base, 1-methyl Acrylate-1-base, 1-(cyclopropyl) ethyl, methoxycarbonyl, 2-butyne base, 2-hydroxyl-1-Methylethyl, 4-(mentioned methylcarbonylamino) Butyl, 3-(mentioned methylcarbonylamino) propyl group, 4-aminobutyl, 1-methyl-2-acrylic, 1-methyl-cyclobutyl, propyl group, 2-methoxy Base ethyl and 2-methyl-propyl.

41. compound as according to any one of claim 33 to 36, wherein R²And R³Formed together with the atom being connected with them 4,5,6,7 or 8 yuan of carbocylic radicals or aryl, described carbocylic radical or aryl are by one or more R^xGroup optionally replaces.

42. compound as according to any one of claim 33 to 40, wherein R³For H.

43. compound as according to any one of claim 33 to 40, wherein R³For C_1-12Alkyl, C_2-12Thiazolinyl, C_2-12Alkynyl, Carbocylic radical, aryl, heterocyclic radical, heteroaryl, halogeno-group ,-OR^a、-SR^a、-N(R^a)₂、-CN、-NO₂、-C(O)R^a、-CO₂R^a、-C(O) N(R^a)₂、-C(O)SR^a、-C(O)C(O)R^a、-C(O)CH₂C(O)R^a、-C(S)N(R^a)₂、-C(S)OR^a、-S(O)R^a、-SO₂R^a、- SO₂N(R^a)₂、-N(R^a)C(O)R^a、-N(R^a)C(O)N(R^a)₂、-N(R^a)SO₂R^a、-N(R^a)SO₂N(R^a)₂、-N(R^a)N(R^a)₂、-N (R^a) C (=N (R^a))N(R^a)₂,-C (=N) N (R^a)₂,-C=NOR^a,-C (=N (R^a))N(R^a)₂、-OC(O)R^aOr-OC (O) N (R^a)₂, wherein R³C_1-12Alkyl, C_2-12Thiazolinyl, C_2-12Alkynyl, carbocylic radical, aryl, heteroaryl and heterocyclic radical are independently of one another By one or more R^xGroup optionally replaces.

44. compound as according to any one of claim 33 to 40, wherein R³For H, C_1-12Alkyl, C_2-12Thiazolinyl, C_2-12Alkynes Base, aryl, heterocyclic radical, heteroaryl, halogeno-group ,-OR^a、-N(R^a)₂、-C(O)R^a、-CO₂R^a、-C(O)N(R^a)₂Or-N (R^a)C(O) R^a, wherein R³C_1-12Alkyl, C_2-12Thiazolinyl, C_2-12Alkynyl, aryl, heteroaryl and heterocyclic radical are independently of one another by one or many Individual R^xGroup optionally replaces.

45. compound as according to any one of claim 33 to 40, wherein R³For H, methyl, chlorine, bromine, carboxyl, formoxyl, Amino carbonyl, furan-3-base, phenyl, benzyl, phenethyl, phenoxy group, 1H-pyrazoles-4-base, 1-(Cvclopropvlmethvl)-1H-pyrrole Azoles-4-base, 1-(1-methylcyclopropyl groups)-1H-pyrazoles-4-base, 5-fluoro-1H-pyrazoles-4-base, 1-(2-phenyl acrylate-2-yl)-1H- Pyrazoles-4-base, 1-(pyridin-3-yl)-1H-pyrazoles-4-base, 1-(pyridin-4-yl)-1H-pyrazoles-4-base, 1-(pyridine-2- Base)-1H-pyrazoles-4-base, 1-[1-(N-methylaminocarbonyl)-1,1-dimethyl methyl]-1H-pyrazoles-4-base, the fluoro-1-of 5-be different Propyl group-1H-pyrazoles-4-base, 1-(Cvclopropvlmethvl)-1H-pyrazoles-5-base, 1-(Cvclopropvlmethvl)-1H-pyrazole-3-yl, 1- (tetrahydrochysene-2H-thiapyran-4-base)-1H-pyrazoles-4-base, 1-(1,1-dioxidotetrahydro-2H-thiapyran-4-base)-1H-pyrazoles-4-base, 1-((6-(3-oxo but-1-ene-1-base) pyridine-2-base) methyl)-1H-pyrazoles-4-base, 3-iodophenyl, methylaminocarbonyl, 3-methyl isophthalic acid, 2,4-diazole-5-base, 5-methyl isophthalic acid, 3,4-diazole-2-base, 1H-imidazoles-2-base, N-(benzoyl first Base) amino carbonyl, 5-phenyl azoles-2-base, 1-cyclohexyl pyrazoles-4-base, 1-isopropylpyrazol-4-base, xenyl-3-base, 3-((4-fluorophenyl) amino) phenyl, 3-(2-oxo-pyrrolidine-1-base) phenyl, 3-(mentioned methylcarbonylamino)-5-phenyl, Phenyl amino, piperidin-1-yl, methoxy, ethoxyl methyl, ethoxy carbonyl, 3-methoxy-propyl, benzyloxycarbonyl group, three Methyl fluoride, 3-furyl, ethyl aminocarbonyl, methylol, 3-hydroxypropyl, 2-ethoxy, Methylaminomethyl, benzofuran- 3-base, 1-phenyl-1H-pyrazole-3-yl, 5-cyclopropyl furan-2-base, 2-methylfuran-3-base, 1-phenyl-1H-pyrazoles-4- Base, 1-ethyl-1H-pyrazoles-4-base, 1-methyl-6-oxo-1,6-dihydropyridine-3-base, furan-2-base, 5-benzofurane- 2-base, 1-isopropyl-1H-pyrazoles-4-base, pyrimidine-5-base, 5-picoline-3-base, 1-methyl isophthalic acid H-pyrazole-3-yl, 4-benzene Base furan-2-base, 2-fluorophenyl, 4-cyano-phenyl, 4-methoxyphenyl, 4-(trifluoromethyl) phenyl, 4-fluorophenyl, 1-benzyl Base-1H-pyrazoles-4-base, 5-chloropyridine-3-base, 5-fluorine pyridin-3-yl, acrylate-1-alkene-2-base, vinyl, 1-methyl isophthalic acid H-pyrrole Azoles-5-base, 4-(methylol) furan-2-base, 3-cyano-phenyl, 1H-pyrazoles-5-base, 2,5-dihydrofuran-3-base, thiophene-3- Base, thiophene-2-base, 1-methyl isophthalic acid H-pyrazoles-4-base, 5-methylfuran-2-base, 5-(methylol) furan-2-base, 3-(trifluoro Methyl) phenyl, 3-methoxyphenyl, 3-fluorophenyl, pyridin-3-yl, 1-(methyl sulphonyl)-1H-pyrazoles-4-base, 1-ring penta Base-1H-pyrazoles-4-base, 1-(thiene-3-yl methyl)-1H-pyrazoles-4-base, the chloro-3-of 4-(morpholine-4-carbonyl) phenyl, 3-are chloro- 4-(cyclopropylaminocarbonyl) phenyl, 1-(1-hydroxy-2-methyl acrylate-2-yl)-1H-pyrazoles-4-base, 1-(3-methoxybenzyl Base)-1H-pyrazoles-4 base, 1-(pyridin-4-yl methyl)-1H-pyrazoles-4-base, 1-(2-chlorobenzyl)-1H-pyrazoles-4-base, 1- (3-phenoxy benzyl)-1H-pyrazoles-4-base, 1-(4-phenoxy benzyl)-1H-pyrazoles-4-base, 1-cyclohexyl-1H-pyrazoles-4- Base, 1-(1-phenylethyl)-1H-pyrazoles-4-base, 1-cyclobutyl-1H-pyrazoles-4-base, 1-(sec-butyl)-1H-pyrazoles-4-base, The fluoro-3-of 4-(pyrrolidine-1-carbonyl) phenyl, 1-(Cyclopropylsulfonyl)-1H-pyrazole-3-yl, 1-(cyclopropane carbonyl)-1H-pyrrole Azoles-3-base, 1-(2-cyclopropylethyl)-1H-pyrazoles-4-base, 1-([1,1'-xenyl]-3-ylmethyl)-1H-pyrazoles-4- Base, 1-phenethyl-1H-pyrazoles-4-base, 1-(2 methoxy-benzyl)-1H-pyrazoles-4-base, 1-(4-methoxy-benzyl)-1H-pyrrole Azoles-4-base, 1-(tert-butyl group)-1H-pyrazoles-4-base, 3,4-3,5-dimethylphenyl, 3-chloro-4-ethoxyl phenenyl, 4-methoxyl group-3- Aminomethyl phenyl, 2-methyl benzo [d] thiazole-5-base, 1-(2-phenoxy benzyl)-1H-pyrazoles-4-base, 1-(phenyl sulfonyl)- 1H-pyrazoles-4-base, 1-benzoyl-1H-pyrazoles-4-base, 1-benzhydryl-1H-pyrazoles-4-base, 1-([1,1'-biphenyl Base]-2-ylmethyl)-1H-pyrazoles-4-base, 1-(cyclohexyl methyl)-1H-pyrazoles-4-base, 1-(pyridin-3-yl methyl)-1H- Pyrazoles-4-base, benzofuran-2-base, (E)-styryl, 5-ethyl furan-2-base, 1-(2-methoxy ethyl)-1H-pyrrole Azoles-4-base, 1-(naphthalene-1-ylmethyl)-1H-pyrazoles-4-base, 1-([1,1'-xenyl]-4-ylmethyl)-1H-pyrazoles-4-base, 3-Phenoxyphenyl, phenylene-ethynylene, 3,4-Dichlorobenzene base, 3-chloro-4-methoxy phenyl, 3-methoxyl group-4-aminomethyl phenyl, 1- (thiazole-4-yl methyl)-1H-pyrazoles-4-base, 1H-indazole-5-base, 3,4-Dimethoxyphenyl, 4-methoxyl group-3,5-diformazan Base phenyl, 1-(oxetanes-3-base)-1H-pyrazoles-4-base, 1-(2-luorobenzyl)-1H-pyrazoles-4-base, 1-(4-fluorine benzyl Base)-1H-pyrazoles-4-base, 1-(Methoxycarbonylmethyl)-1H-pyrazoles-4-base, 1-(2-(dimethylamino) ethyl)-1H-pyrrole Azoles-4-base, 3-cyano group-4-aminomethyl phenyl, benzo [d] [1,3] dioxole-5-base, 2,3-Dihydrobenzofuranes-5- Base, 1-(3-luorobenzyl)-1H-pyrazoles-4-base, 1-(thiophene-2-ylmethyl)-1H-pyrazoles-4-base, 1-(2,2,2-trifluoro second Base)-1H-pyrazoles-4-base, 1-(3-chlorobenzyl)-1H-pyrazoles-4-base, 1-isobutyl group-1H-pyrazoles-4-base, 1-(3,3,3-tri- Fluoropropyl)-1H-pyrazoles-4-base, 1-(difluoromethyl)-1H-pyrazoles-4-base, 1-(2-cyano ethyl)-1H-pyrazoles-4-base, 4- Cyclopropyl furan-2-base, 1H-pyrroles's-3-base, 2,2-difluoro benzo [d] [1,3] dioxole-5-base, the fluoro-4-of 3- (amino carbonyl) phenyl, 3-fluoro-4-(methyl sulphonyl) phenyl, 3-chloro-4-(trifluoromethoxy) phenyl, 5-fluoro-3-(amino carbonyl Base) phenyl, 3-(hydroxymethyl)-4-methoxyphenyl, 1-(methyl sulphonyl)-1H-pyrroles's-3-base, 1-methyl isophthalic acid H-pyrroles- 3-base, 1H-indole-2-base, cyclopropylcarbonylamino, benzoyl-amido, 3-bromophenyl, 3-(1-methyl-pyrazol-4-yl) benzene Base, 3-(1-isopropylpyrazol-4-base) phenyl, 4-phenyl, 4-(4-fluoroanilino) phenyl, 3-(tert-butoxycarbonyl ammonia Base) phenyl, 1-acetyl group-1,2,3,6-tetrahydropyridine-4-base, 1-propiono-1,2,3,6-tetrahydropyridine-4-base, 1-propylene Acyl group-1,2,3,6-tetrahydropyridine-4-base, 1-methyl isophthalic acid, 2,3,6-tetrahydropyridine-4-base, 1-((2-methylthiazol-4-base) Methyl)-1H-pyrazoles-4-base, 1-(2-(acetyl-amino) ethyl)-1H-pyrazoles-4-base, 3,5-Dichlorobenzene base, the fluoro-4-of 2- (methyl sulphonyl) phenyl, 1-(tertiary pentyl)-1H-pyrazoles-4-base, 3-(2-morpholinoethyl) phenyl, 3-(2-(dimethylamino Base) ethyl) phenyl, 1-(1-(thiazole-4-yl) ethyl)-1H-pyrazoles-4-base, 1-(tetrahydrochysene-2H-pyrans-4-base)-1H-pyrrole Azoles-4-base, 3-methoxyl group-4-(trifluoromethyl) phenyl, 3-methoxycarbonyl-4-chlorphenyl, 4-(trifluoromethoxy) phenyl, 3- Methyl-4-(trifluoromethoxy) phenyl, 4-cyclopropyl-3-(trifluoromethyl) phenyl, 2,2-dimethyl-2,3-dihydrobenzo furan Mutter-5-base, 3,5-Dimethoxyphenyl, 3,4-difluorophenyl, 4-xenyl, 3-chloro-5-fluorophenyl, 3,5-double (trifluoromethyl) Phenyl, 3-fluoro-5-methoxyphenyl, 3-(amino carbonyl) phenyl, 4-(cyclo propyl methoxy) phenyl, 2-fluoro-5-(benzyloxy carbonyl Base) phenyl, 3-(1H-pyrazol-1-yl) phenyl, 1-(2-hydroxycyclopent base)-1H-pyrazoles-4-base, 3-(N-methylamino sulphonyl Base) phenyl, 4-(2-hydroxyl acrylate-2-yl) phenyl, 2-(trifluoromethyl) pyridin-4-yl, 6-phenoxypyridines-3-base, 2-methoxy Yl pyridines-4-base, 4-methyl-2-phenyl thiazole-5-base, 3-amino-5-cyano phenyl, 1-(oxolane-3-base, 3-(N-second Base amino carbonyl) phenyl, 3-(amino carbonyl methyl) phenyl, 6-phenylpyridine-3-base, 1-(tetrahydrochysene-2H-pyrans-3-base)- 1H-pyrazoles-4-base, 1-(1-methoxy propyl-2-base)-1H-pyrazoles-4-base, 1-(2-ethoxyethyl group)-1H-pyrazoles-4-base, 1-acetyl group-2,5-dihydro-1 h-pyrazole-3-base, 1-acetyl group-1,2,5,6-tetrahydropyridine-3-base, 1-propiono-1,2,5, 6-tetrahydropyridine-3-base, 1-propiono-2,5-dihydro-1H-pyrroles's-3-base, 1-((1S, 3S)-3-hydroxycyclobutyl)-1H-pyrrole Azoles-4-base, 2,5-dihydro-1H-pyrroles's-3-base, 1,2,5,6-tetrahydropyridine-3-base, 1-methyl isophthalic acid, 2,5,6-tetrahydropyridine- 3-base, 1-acryloyl group-1,2,5,6-tetrahydropyridine-3-base, 1-acryloyl group-2,5-dihydro-1H-pyrroles's-3-base, 4-are chloro- 3,5-3,5-dimethylphenyl, 4-cyano group-3-aminomethyl phenyl, 1-oxo-2,3-dihydro-1H-indenes-5-base, 3,4-are double (trifluoromethyl) Phenyl, 3-methyl-4-(trifluoromethyl) phenyl, 1-(benzo [b] thiophene-7-ylmethyl)-1H-pyrazoles-4-base, 4-fluoro-3-(N- Cyclohexylaminocarbonyl) phenyl, 4-morphlinophenyl, 4-(4-(tert-butoxycarbonyl) piperazine-1-base) phenyl, 3-chloro-5-first Base phenyl, 3-(methyl sulphonyl) phenyl, 4-(Methylsulfonylamino) phenyl, 4-(morpholinomethyl) phenyl, 3-morpholino Phenyl, 1-(2-(ethenylcarbonylamino) ethyl)-1H-pyrazoles-4-base, 1-(2-amino-ethyl)-1H-pyrazoles-4-base, 3-ring Propyl group-4-aminomethyl phenyl, 3-ethoxyl phenenyl, 3-(methylol) phenyl, 1-(2-(tertbutyloxycarbonylamino) ethyl)-1H- Pyrazoles-4-base, 3-benzene ethoxyl phenenyl, 1,2,3,6-tetrahydropyridine-4-base, 1-(2-(vinylsulfonyl amino) ethyl)- 1H-pyrazoles-4-base, 4-(phenyl amino) phenyl, 3-methyl isophthalic acid H-pyrazoles-4-base, 4-(benzyloxy) phenyl, 3,5-difluorobenzene Base, 3-fluoro-5-trifluoromethyl, 3-(ethylsulfonyl) phenyl, 3-(trifluoromethoxy) phenyl, 1-(thiazole-5-Ji Jia Base)-1H-pyrazoles-4-base, p-methylphenyl, 4-cyclopropyl phenyl, 4-(ethylsulfonyl) phenyl, 1-(6-vinylpyridine-2- Base) methyl)-1H-pyrazoles-4-base, 6-(benzyloxy) pyridin-3-yl, 1-(tert-butoxycarbonyl)-2,5-dihydro-1H-pyrroles- 3-base, 1-(2-hydroxyl-1-phenylethyl)-1H-pyrazoles-4-base, 1-(2-cyano group-1-phenylethyl)-1H-pyrazoles-4-base, 6- Cyclopropyl pyridine-3-base, 4-cyano group-3-methoxyphenyl, 4-methoxyl group-3-(trifluoromethyl) phenyl, 4-chlorphenyl, 1-(3, 4-difluorobenzyl)-1H-pyrazoles-4-base, 4-methyl-3-(trifluoromethyl) phenyl, 4-(pyrrolidine-1-carbonyl) phenyl, 4-be (different Propylaminocarbonyl) phenyl, 4-(4-methylpiperazine-1-yl) phenyl, 3-chloro-5-cyano-phenyl, 3-(pyrrolidine-1-carbonyl) benzene Base, 3-(Methylsulfonylamino methyl) phenyl, 3-(1H-pyrazoles-5-base) phenyl, 4-(methyl sulphonyl) phenyl, 4-(ring third Base amino carbonyl) phenyl, 1-(2-fluoro ethyl)-1H-pyrazoles-4-base, 3-(cyclo propyl methoxy) phenyl, 3-(benzyloxy) benzene Base, 3-(morpholinomethyl) phenyl, 3-(phenoxymethyl) phenyl, 1-(3-fluorophenyl)-1H-pyrazoles-4-base, 2-cyclopropyl second Thiazolinyl, 6-(trifluoromethyl) pyridin-3-yl, 1-(4-fluorophenyl)-1H-pyrazoles-4-base, 2,4-dimethylthiazole-5-base, 1-third Base-1H-pyrazoles-4-base, 1-butyl-1H-pyrazoles-4-base, 1-(2-(phenyl amino) ethyl)-1H-pyrazoles-4-base, 4-(amino Carbonyl) phenyl, 4-(N-methylaminocarbonyl) phenyl, the fluoro-4-of 3-(N-methylaminocarbonyl) phenyl, 1-(2-(3,3-difluoro nitrogen Azetidine-1-base) ethyl)-1H-pyrazoles-4-base, 1-(2-(3,3-difluoropyrrolidin-1-base) ethyl)-1H-pyrazoles-4- Base, 1-(2-((2,2,2-trifluoroethyl) amino) ethyl)-1H-pyrazoles-4-base, 1-acrylic, 3-(mentioned methylcarbonylamino) benzene Base, 4-(Methylsulfonylamino) phenyl, 4-(morpholine-4-carbonyl) phenyl, 4-(4-Acetylpiperazine-1-base) phenyl, 1-(2, 2-bis-fluoro ethyl)-1H-pyrazoles-4-base, 5-isopropyl furan-2-base, 1-(3,3-Difluorocyclopentyl)-1H-pyrazoles-4-base, 1- ((1S, 3R)-3-hydroxycyclopent base)-1H-pyrazoles-4-base, 1-((1S, 3S)-3-hydroxycyclopent base)-1H-pyrazoles-4-base, 3- (1H-pyrazoles-4-base) phenyl, 5-bromine furan-2-base, 3-(phenyl amino) phenyl, 2-methylthiazol-5-base, 3-(phenylacetylene Base) phenyl, 3-phenethyl phenyl, 1-(3-fluorine cyclopenta)-1H-pyrazoles-4-base, 1-(1-methoxyl group-2-methyl-prop-2-base)- 1H-pyrazoles-4-base, 1-(1-acryloyl group azetidine-3-base)-1H-pyrazoles-4-base, 1-(1-propiono azetidin Alkane-3-base)-1H-pyrazoles-4-base, 6-oxo-1,6-dihydropyridine-3-base, 4-(piperazine-1-base) phenyl, 1-(1-fluoro-2-first Base acrylate-2-yl)-1H-pyrazoles-4-base, 3-(trifluoromethyl)-1H-pyrazoles-4-base, 3,5-3,5-dimethylphenyl, 4-(morpholino sulphur Acyl group) phenyl, 3-(4-methyl piperazine-1-carbonyl) phenyl, 3-(2-hydroxyl acrylate-2-yl) phenyl, 1-isopropyl-3-methyl isophthalic acid H- Pyrazoles-4-base, 1-isopropyl-5-methyl isophthalic acid H-pyrazoles-4-base, 3-cyclopropyl-1H-pyrazoles-5-base, 5-methoxycarbonyl pyrrole Cough up-3-base, 3-cyclopropyl-1-isopropyl-1H-pyrazoles-5-base, 5-cyclopropyl-1-isopropyl-1H-pyrazole-3-yl, 1-isopropyl Base-5-(methoxycarbonyl) pyrroles-3-base, 1-methyl-3-(trifluoromethyl)-1H-pyrazoles-5-base, 1-isopropyl-1H-pyrazoles- 3-base, 1-cyclopenta-5-cyclopropyl-1H-pyrazole-3-yl, 1-cyclopenta-3-cyclopropyl-1H-pyrazoles-5-base, 1-cyclopenta- 1H-pyrazole-3-yl, 1-isopropyl-1H-pyrazoles-5-base, 1-isopropyl-5-(N-methylaminocarbonyl) pyrroles's-3-base, 1-are different Propyl group-5-(N, N-Dimethylaminocarbonyl) pyrroles's-3-base, 1-(2-cyclopropylethyl)-1H-pyrazole-3-yl, 1-(2-ring third Base ethyl)-1H-pyrazoles-5-base, 1-ethyl-1H-pyrazole-3-yl, 3-(3,3-dimethyl-2-oxo-pyrrolidine-1-base) benzene Base, 3-(2-oxo-3-Phenylpyrrolidine-1-base) phenyl, 3-((E)-styryl) phenyl, 3-(3-cyano-phenyl) phenyl, 3-(3-(Methylsulfonylamino) phenyl) phenyl, 3-(4-(Methylsulfonylamino) phenyl) phenyl or 3-(4-(N-methyl ammonia Base sulfonyl) phenyl) phenyl.

46. compound as according to any one of claim 33 to 40, wherein R³For aryl or heteroaryl, wherein aryl and miscellaneous Aryl is each by one or more group R^XOptionally replacing, condition is R³It not phenyl, fluorophenyl, chlorphenyl, pyridine radicals, nitre Base phenyl or propyl group isoxazole.

47. compound as according to any one of claim 33 to 40, wherein R³For by R^xOptionally substituted pyrazoles-4-base.

48. compound as according to any one of claim 33 to 47, wherein R^xFor by one or more independently selected from following The substituted C of group_1-6Alkyl: R^xa, oxo base, halogeno-group ,-NO₂、-N(R^v)₂、-CN、-C(O)-N(R^v)₂、-S(O)-N (R^v)₂、-S(O)₂-N(R^v)₂、-O-R^v、-S-R^v、-O-C(O)-R^v、-C(O)-R^v、-C(O)-O-R^v、-S(O)-R^v、-S(O)₂- R^v、-C(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-N(R^v)-C(O)-R^v、N(R^v)-C(O)-OR^v、-N(R^v)-S(O)-R^vAnd-N (R^v)-S(O)₂-R^v。

49. compound as according to any one of claim 33 to 47, wherein R^xFor by R^xaOptionally substituted C_1-6Alkyl.

50. compound as according to any one of claim 33 to 40, wherein R³For 1H-pyrazoles-4-base, 1-(cyclopropyl first Base)-1H-pyrazoles-4-base, 1-(1-methylcyclopropyl groups)-1H-pyrazoles-4-base, 5-fluoro-1H-pyrazoles-4-base, 1-(2-phenyl acrylate- 2-yl)-1H-pyrazoles-4-base, 1-(pyridin-3-yl)-1H-pyrazoles-4-base, 1-(pyridin-4-yl)-1H-pyrazoles-4-base, 1- (pyridine-2-base)-1H-pyrazoles-4-base, 1-[1-(N-methylaminocarbonyl)-1,1-dimethyl methyl]-1H-pyrazoles-4-base, 5-fluoro-1-isopropyl-1H-pyrazoles-4-base, 1-(Cvclopropvlmethvl)-1H-pyrazoles-5-base, 1-(Cvclopropvlmethvl)-1H-pyrrole Azoles-3-base, 1-(tetrahydrochysene-2H-thiapyran-4-base)-1H-pyrazoles-4-base, 1-(1,1-dioxidotetrahydro-2H-thiapyran-4-base)-1H- Pyrazoles-4-base, 1-((6-(3-oxo but-1-ene-1-base) pyridine-2-base) methyl)-1H-pyrazoles-4-base, 3-iodophenyl, 3- Methyl isophthalic acid, 2,4-diazole-5-base, 5-methyl isophthalic acid, 3,4-diazole-2-base, 1H-imidazoles-2-base, 5-phenyl azoles-2-base, 1-cyclohexyl pyrazoles-4-base, 1-isopropylpyrazol-4-base, xenyl-3-base, 3-((4-fluorophenyl) amino) phenyl, 3-(2- Oxo-pyrrolidine-1-base) phenyl, 3-(mentioned methylcarbonylamino)-5-phenyl, 3-furyl, benzofuran-3-base, 1-benzene Base-1H-pyrazole-3-yl, 5-cyclopropyl furan-2-base, 2-methylfuran-3-base, 1-phenyl-1H-pyrazoles-4-base, 1-ethyl- 1H-pyrazoles-4-base, 1-methyl-6-oxo-1,6-dihydropyridine-3-base, furan-2-base, 5-benzofurane-2-base, 1-isopropyl Base-1H-pyrazoles-4-base, pyrimidine-5-base, 5-picoline-3-base, 1-methyl isophthalic acid H-pyrazole-3-yl, 4-benzofurane-2- Base, 2-fluorophenyl, 4-cyano-phenyl, 4-methoxyphenyl, 4-(trifluoromethyl) phenyl, 4-fluorophenyl, 1-benzyl-1H-pyrazoles- 4-base, 5-chloropyridine-3-base, 5-fluorine pyridin-3-yl, 1-methyl isophthalic acid H-pyrazoles-5-base, 4-(methylol) furan-2-base, 3-cyanogen Base phenyl, 2,5-dihydrofuran-3-base, thiene-3-yl, thiophene-2-base, 1-methyl isophthalic acid H-pyrazoles-4-base, 5-methylfuran- 2-base, 5-(methylol) furan-2-base, 3-(trifluoromethyl) phenyl, 3-methoxyphenyl, 3-fluorophenyl, pyridin-3-yl, 1- (methyl sulphonyl)-1H-pyrazoles-4-base, 1-cyclopenta-1H-pyrazoles-4-base, 1-(thiene-3-yl methyl)-1H-pyrazoles-4- The chloro-3-of base, 4-(morpholine-4-carbonyl) phenyl, 3-chloro-4-(cyclopropylaminocarbonyl) phenyl, 1-(1-hydroxy-2-methyl acrylate-2- Base)-1H-pyrazoles-4-base, 1-(3-methoxy-benzyl)-1H-pyrazoles-4 base, 1-(pyridin-4-yl methyl)-1H-pyrazoles-4-base, 1-(2-chlorobenzyl)-1H-pyrazoles-4-base, 1-(3-phenoxy benzyl)-1H-pyrazoles-4-base, 1-(4-phenoxy benzyl)-1H- Pyrazoles-4-base, 1-cyclohexyl-1H-pyrazoles-4-base, 1-(1-phenylethyl)-1H-pyrazoles-4-base, 1-cyclobutyl-1H-pyrazoles- 4-base, 1-(sec-butyl)-1H-pyrazoles-4-base, the fluoro-3-of 4-(pyrrolidine-1-carbonyl) phenyl, 1-(Cyclopropylsulfonyl)-1H- Pyrazole-3-yl, 1-(cyclopropane carbonyl)-1H-pyrazole-3-yl, 1-(2-cyclopropylethyl)-1H-pyrazoles-4-base, 1-([1,1'- Xenyl]-3-ylmethyl)-1H-pyrazoles-4-base, 1-phenethyl-1H-pyrazoles-4-base, 1-(2 methoxy-benzyl)-1H-pyrazoles- 4-base, 1-(4-methoxy-benzyl)-1H-pyrazoles-4-base, 1-(tert-butyl group)-1H-pyrazoles-4-base, 3,4-3,5-dimethylphenyl, 3- Chloro-4-ethoxyl phenenyl, 4-methoxyl group-3-aminomethyl phenyl, 2-methyl benzo [d] thiazole-5-base, 1-(2-phenoxy benzyl)- 1H-pyrazoles-4-base, 1-(phenyl sulfonyl)-1H-pyrazoles-4-base, 1-benzoyl-1H-pyrazoles-4-base, 1-benzhydryl- 1H-pyrazoles-4-base, 1-([1,1'-xenyl]-2-ylmethyl)-1H-pyrazoles-4-base, 1-(cyclohexyl methyl)-1H-pyrazoles- 4-base, 1-(pyridin-3-yl methyl)-1H-pyrazoles-4-base, benzofuran-2-base, 5-ethyl furan-2-base, 1-(2-methoxyl group Ethyl)-1H-pyrazoles-4-base, 1-(naphthalene-1-ylmethyl)-1H-pyrazoles-4-base, 1-([1,1'-xenyl]-4-ylmethyl)- 1H-pyrazoles-4-base, 3-Phenoxyphenyl, phenylene-ethynylene, 3,4-Dichlorobenzene base, 3-chloro-4-methoxy phenyl, 3-methoxyl group- 4-aminomethyl phenyl, 1-(thiazole-4-yl methyl)-1H-pyrazoles-4-base, 1H-indazole-5-base, 3,4-Dimethoxyphenyl, 4-first Epoxide-3,5-3,5-dimethylphenyl, 1-(oxetanes-3-base)-1H-pyrazoles-4-base, 1-(2-luorobenzyl)-1H-pyrazoles-4- Base, 1-(4-luorobenzyl)-1H-pyrazoles-4-base, 1-(Methoxycarbonylmethyl)-1H-pyrazoles-4-base, 1-(2-(dimethylamino Base) ethyl)-1H-pyrazoles-4-base, 3-cyano group-4-aminomethyl phenyl, benzo [d] [1,3] dioxole-5-base, 2,3- Dihydrobenzofuranes-5-base, 1-(3-luorobenzyl)-1H-pyrazoles-4-base, 1-(thiophene-2-ylmethyl)-1H-pyrazoles-4-base, 1- (2,2,2-trifluoroethyl)-1H-pyrazoles-4-base, 1-(3-chlorobenzyl)-1H-pyrazoles-4-base, 1-isobutyl group-1H-pyrazoles-4- Base, 1-(3,3,3-trifluoro propyl)-1H-pyrazoles-4-base, 1-(difluoromethyl)-1H-pyrazoles-4-base, 1-(2-cyano ethyl)- 1H-pyrazoles-4-base, 4-cyclopropyl furan-2-base, 2,2-difluoro benzo [d] [1,3] dioxole-5-base, 3-are fluoro- 4-(amino carbonyl) phenyl, 3-fluoro-4-(methyl sulphonyl) phenyl, 3-chloro-4-(trifluoromethoxy) phenyl, 5-fluoro-3-(amino Carbonyl) phenyl, 3-(hydroxymethyl)-4-methoxyphenyl, 1-(methyl sulphonyl)-1H-pyrroles's-3-base, 1-methyl isophthalic acid H-pyrrole Cough up-3-base, 3-bromophenyl, 3-(1-methyl-pyrazol-4-yl) phenyl, 3-(1-isopropylpyrazol-4-base) phenyl, 4-phenyl benzene Base, 4-(4-fluoroanilino) phenyl, 3-(tertbutyloxycarbonylamino) phenyl, 1-acetyl group-1,2,3,6-tetrahydropyridine-4- Base, 1-propiono-1,2,3,6-tetrahydropyridine-4-base, 1-acryloyl group-1,2,3,6-tetrahydropyridine-4-base, 1-methyl isophthalic acid, 2,3,6-tetrahydropyridine-4-base, 1-((2-methylthiazol-4-base) methyl)-1H-pyrazoles-4-base, 1-(2-(acetyl-amino) Ethyl)-1H-pyrazoles-4-base, 3,5-Dichlorobenzene base, 2-fluoro-4-(methyl sulphonyl) phenyl, 1-(tertiary pentyl)-1H-pyrazoles-4- Base, 3-(2-morpholinoethyl) phenyl, 3-(2-(dimethylamino) ethyl) phenyl, 1-(1-(thiazole-4-yl) ethyl)-1H- Pyrazoles-4-base, 1-(tetrahydrochysene-2H-pyrans-4-base)-1H-pyrazoles-4-base, 3-methoxyl group-4-(trifluoromethyl) phenyl, 3-methoxy Base carbonyl-4-chlorphenyl, 4-(trifluoromethoxy) phenyl, 3-methyl-4-(trifluoromethoxy) phenyl, 4-cyclopropyl-3-(trifluoro Methyl) phenyl, 2,2-dimethyl-2,3-Dihydrobenzofuranes-5-base, 3,5-Dimethoxyphenyl, 3,4-difluorophenyl, 4-connection Phenyl, 3-chloro-5-fluorophenyl, 3,5-double (trifluoromethyl) phenyl, 3-fluoro-5-methoxyphenyl, 3-(amino carbonyl) phenyl, 4- (cyclo propyl methoxy) phenyl, 2-fluoro-5-(benzyloxycarbonyl) phenyl, 3-(1H-pyrazol-1-yl) phenyl, 1-(2-hydroxycyclopent Base)-1H-pyrazoles-4-base, 3-(N-methylaminosulfonyl) phenyl, 4-(2-hydroxyl acrylate-2-yl) phenyl, 2-(trifluoromethyl) Pyridin-4-yl, 6-phenoxypyridines-3-base, 2-methoxypyridine-4-base, 4-methyl-2-phenyl thiazole-5-base, 3-amino- 5-cyano-phenyl, 1-(oxolane-3-base, 3-(N-ethyl aminocarbonyl) phenyl, 3-(amino carbonyl methyl) phenyl, 6-benzene Yl pyridines-3-base, 1-(tetrahydrochysene-2H-pyrans-3-base)-1H-pyrazoles-4-base, 1-(1-methoxy propyl-2-base)-1H-pyrazoles-4- Base, 1-(2-ethoxyethyl group)-1H-pyrazoles-4-base, 1-acetyl group-2,5-dihydro-1 h-pyrazole-3-base, 1-acetyl group-1,2, 5,6-tetrahydropyridine-3-base, 1-propiono-1,2,5,6-tetrahydropyridine-3-base, 1-propiono-2,5-dihydro-1H-pyrroles-3- Base, 1-((1S, 3S)-3-hydroxycyclobutyl)-1H-pyrazoles-4-base, 2,5-dihydro-1H-pyrroles's-3-base, 1,2,5,6-tetrahydrochysene pyrrole Pyridine-3-base, 1-methyl isophthalic acid, 2,5,6-tetrahydropyridine-3-base, 1-acryloyl group-1,2,5,6-tetrahydropyridine-3-base, 1-propylene Acyl group-2,5-dihydro-1H-pyrroles's-3-base, 4-chloro-3,5-3,5-dimethylphenyl, 4-cyano group-3-aminomethyl phenyl, 1-oxo-2,3- Double (trifluoromethyl) phenyl of dihydro-1H-indenes-5-base, 3,4-, 3-methyl-4-(trifluoromethyl) phenyl, 1-(benzo [b] thiophene- 7-ylmethyl)-1H-pyrazoles-4-base, the fluoro-3-of 4-(N-cyclohexylaminocarbonyl) phenyl, 4-morphlinophenyl, 4-(4-(tertiary fourth Epoxide carbonyl) piperazine-1-base) phenyl, 3-chloro-5-aminomethyl phenyl, 3-(methyl sulphonyl) phenyl, 4-(Methylsulfonylamino) Phenyl, 4-(morpholinomethyl) phenyl, 3-morphlinophenyl, 1-(2-(ethenylcarbonylamino) ethyl)-1H-pyrazoles-4-base, 1-(2-amino-ethyl)-1H-pyrazoles-4-base, 3-cyclopropyl-4-aminomethyl phenyl, 3-ethoxyl phenenyl, 3-(hydroxymethyl) benzene Base, 1-(2-(tertbutyloxycarbonylamino) ethyl)-1H-pyrazoles-4-base, 3-benzene ethoxyl phenenyl, 1,2,3,6-tetrahydropyridine- 4-base, 1-(2-(vinylsulfonyl amino) ethyl)-1H-pyrazoles-4-base, 4-(phenyl amino) phenyl, 3-methyl isophthalic acid H-pyrrole Azoles-4-base, 4-(benzyloxy) phenyl, 3,5-difluorophenyl, 3-fluoro-5-trifluoromethyl, 3-(ethylsulfonyl) phenyl, 3- (trifluoromethoxy) phenyl, 1-(thiazole-5-ylmethyl)-1H-pyrazoles-4-base, p-methylphenyl, 4-cyclopropyl phenyl, 4-(ethyl Sulfonyl) phenyl, 1-(6-vinylpyridine-2-base) methyl)-1H-pyrazoles-4-base, 6-(benzyloxy) pyridin-3-yl, 1-(uncle Butoxy carbonyl)-2,5-dihydro-1H-pyrroles's-3-base, 1-(2-hydroxyl-1-phenylethyl)-1H-pyrazoles-4-base, 1-(2-cyanogen Base-1-phenylethyl)-1H-pyrazoles-4-base, 6-cyclopropyl pyridine-3-base, 4-cyano group-3-methoxyphenyl, 4-methoxyl group-3- (trifluoromethyl) phenyl, 4-chlorphenyl, 1-(3,4-difluorobenzyl)-1H-pyrazoles-4-base, 4-methyl-3-(trifluoromethyl) benzene Base, 4-(pyrrolidine-1-carbonyl) phenyl, 4-(isopropylaminocarbonyl) phenyl, 4-(4-methylpiperazine-1-yl) phenyl, 3-are chloro- 5-cyano-phenyl, 3-(pyrrolidine-1-carbonyl) phenyl, 3-(Methylsulfonylamino methyl) phenyl, 3-(1H-pyrazoles-5-base) Phenyl, 4-(methyl sulphonyl) phenyl, 4-(cyclopropylaminocarbonyl) phenyl, 1-(2-fluoro ethyl)-1H-pyrazoles-4-base, 3- (cyclo propyl methoxy) phenyl, 3-(benzyloxy) phenyl, 3-(morpholinomethyl) phenyl, 3-(phenoxymethyl) phenyl, 1-(3- Fluorophenyl)-1H-pyrazoles-4-base, 2-cyclopropylethenyl, 6-(trifluoromethyl) pyridin-3-yl, 1-(4-fluorophenyl)-1H-pyrrole Azoles-4-base, 2,4-dimethylthiazole-5-base, 1-propyl group-1H-pyrazoles-4-base, 1-butyl-1H-pyrazoles-4-base, 1-(2-(benzene Base amino) ethyl)-1H-pyrazoles-4-base, 4-(amino carbonyl) phenyl, 4-(N-methylaminocarbonyl) phenyl, 3-fluoro-4-(N- Methylaminocarbonyl) phenyl, 1-(2-(3,3-difluoro azetidine-1-base) ethyl)-1H-pyrazoles-4-base, 1-(2-(3,3- Difluoropyrrolidin-1 base) ethyl)-1H-pyrazoles-4-base, 1-(2-((2,2,2-trifluoroethyl) amino) ethyl)-1H-pyrazoles-4- Base, 1-acrylic, 3-(mentioned methylcarbonylamino) phenyl, 4-(Methylsulfonylamino) phenyl, 4-(morpholine-4-carbonyl) phenyl, 4-(4-Acetylpiperazine-1-base) phenyl, 1-(2,2-bis-fluoro ethyl)-1H-pyrazoles-4-base, 5-isopropyl furan-2-base, 1- (3,3-Difluorocyclopentyl)-1H-pyrazoles-4-base, 1-((1S, 3R)-3-hydroxycyclopent base)-1H-pyrazoles-4-base, 1-((1S, 3S)-3-hydroxycyclopent base)-1H-pyrazoles-4-base, 3-(1H-pyrazoles-4-base) phenyl, 5-bromine furan-2-base, 3-(phenylamino Base) phenyl, 2-methylthiazol-5-base, 3-(phenylene-ethynylene) phenyl, 3-phenethyl phenyl, 1-(3-fluorine cyclopenta)-1H-pyrrole Azoles-4-base, 1-(1-methoxyl group-2-methyl-prop-2-base)-1H-pyrazoles-4-base, 1-(1-acryloyl group azetidine-3- Base)-1H-pyrazoles-4-base, 1-(1-propiono azetidine-3-base)-1H-pyrazoles-4-base, 6-oxo-1,6-dihydro pyrrole Pyridine-3-base, 4-(piperazine-1-base) phenyl, 1-(1-fluoro-2-methyl-prop-2-base)-1H-pyrazoles-4-base, 3-(trifluoromethyl)- 1H-pyrazoles-4-base, 3,5-3,5-dimethylphenyl, 4-(morpholinosulfonyl) phenyl, 3-(4-methyl piperazine-1-carbonyl) phenyl, 3- (2-hydroxyl acrylate-2-yl) phenyl, 1-isopropyl-3-methyl isophthalic acid H-pyrazoles-4-base, 1-isopropyl-5-methyl isophthalic acid H-pyrazoles-4- Base, 3-cyclopropyl-1H-pyrazoles-5-base, 5-methoxycarbonyl pyrroles's-3-base, 3-cyclopropyl-1-isopropyl-1H-pyrazoles-5- Base, 5-cyclopropyl-1-isopropyl-1H-pyrazole-3-yl, 1-isopropyl-5-(methoxycarbonyl) pyrroles-3-base, 1-methyl-3- (trifluoromethyl)-1H-pyrazoles-5-base, 1-isopropyl-1H-pyrazole-3-yl, 1-cyclopenta-5-cyclopropyl-1H-pyrazole-3-yl, 1-cyclopenta-3-cyclopropyl-1H-pyrazoles-5-base, 1-cyclopenta-1H-pyrazole-3-yl, 1-isopropyl-1H-pyrazoles-5-base, 1- Isopropyl-5-(N-methylaminocarbonyl) pyrroles's-3-base, 1-isopropyl-5-(N, N-Dimethylaminocarbonyl) pyrroles's-3-base, 1-(2-cyclopropylethyl)-1H-pyrazole-3-yl, 1-(2-cyclopropylethyl)-1H-pyrazoles-5-base, 1-ethyl-1H-pyrazoles-3- Base, 3-(3,3-dimethyl-2-oxo-pyrrolidine-1-base) phenyl, 3-(2-oxo-3-Phenylpyrrolidine-1-base) phenyl, 3- ((E)-styryl) phenyl, 3-(3-cyano-phenyl) phenyl, 3-(3-(Methylsulfonylamino) phenyl) phenyl, 3-(4-(first Base sulfuryl amino) phenyl) phenyl or 3-(4-(N-methylaminosulfonyl) phenyl) phenyl.

51. compound as according to any one of claim 33 to 40, wherein R³For by R^xSubstituted pyrazoles-4-base.

52. compound as according to any one of claim 33 to 40, wherein R³Phenyl for being replaced by the following: oxo Base, C_1-6Alkyl, C_2-6Thiazolinyl, C_2-6Alkynyl, carbocylic radical, aryl, heteroaryl, heterocycle ,-N (R^v)₂、-CN、-C(O)-N(R^v)₂、-S (O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-O-R^v、-S-R^v、-O-C(O)-R^v、-O-C(O)-O-R^v、-C(O)-R^v、-C(O)-O- R^v、-S(O)-R^v、-S(O)₂-R^v、-O-C(O)-N(R^v)₂、-N(R^v)-C(O)-OR^v、-N(R^v)-C(O)-N(R^v)₂、-S(O)₂-N (R^v)₂、-N(R^v)-C(O)-R^v、-N(R^v)-S(O)-R^v、-N(R^v)-S(O)₂R^v、-N(R^v)-S(O)-N(R^v)₂Or-N (R^v)-S (O)₂-N(R^v)₂, any of which C_1-6Alkyl, C_2-6Thiazolinyl, C_2-6Alkynyl, carbocylic radical, aryl, heteroaryl and heterocycle by one or Multiple independently selected from R^xa, oxo base, halogeno-group ,-NO₂、-N(R^v)₂、-CN、-C(O)-N(R^v)₂、-S(O)-N(R^v)₂、-S (O)₂-N(R^v)₂、-O-R^v、-S-R^v、-O-C(O)-R^v、-C(O)-R^v、-C(O)-O-R^v、-S(O)-R^v、-S(O)₂-R^v、-C(O)-N (R^v)₂、-S(O)₂-N(R^v)₂、-N(R^v)-C(O)-R^v、-N(R^v)-C(O)-OR^v、-N(R^v)-S(O)-R^v、-N(R^v)-S(O)₂-R^v Or by one or more optionally substituted C of the group independently selected from oxo base and halogeno-group_1-6The group of alkyl optionally takes Generation.

53. compound as according to any one of claim 33 to 47, wherein R^xFor C_2-6Thiazolinyl or C_2-6Alkynyl, the most arbitrarily C_2-6Thiazolinyl and C_2-6Alkynyl by one or more independently selected from R^xa, oxo base, halogeno-group ,-NO₂、-N(R^v)₂、-CN、-C (O)-N(R^v)₂、-S(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-O-R^v、-S-R^v、-O-C(O)-R^v、-C(O)-R^v、-C(O)-O- R^v、-S(O)-R^v、-S(O)₂-R^v、-C(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-N(R^v)-C(O)-R^v、-N(R^v)-C(O)-OR^v、- N(R^v)-S(O)-R^vAnd-N (R^v)-S(O)₂-R^vGroup optionally replace.

54. compound as according to any one of claim 33 to 47, wherein R^xSelected from C_2-6Thiazolinyl, C_2-6Alkynyl, carbocylic radical, Aryl, heteroaryl, heterocycle ,-F ,-Cl ,-Br ,-I ,-NO₂、-N(R^v)₂、-CN、-C(O)-N(R^v)₂、-S(O)-N(R^v)₂、-S (O)₂-N(R^v)₂、-O-R^v、-S-R^v、-O-C(O)-R^v、-O-C(O)-O-R^v、-C(O)-R^v、-C(O)-O-R^v、-S(O)-R^v、-S (O)₂-R^v、-O-C(O)-N(R^v)₂,、-N(R^v)-C(O)-OR^v、-N(R^v)-C(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-N(R^v)-C (O)-R^v、-N(R^v)-S(O)-R^v、-N(R^v)S(O₂)R^v、-N(R^v)-S(O)-N(R^v)₂And-N (R^v)-S(O)₂-N(R^v)₂, its In arbitrary C_2-6Thiazolinyl, C_2-6Alkynyl, carbocylic radical, aryl, heteroaryl and heterocyclic radical by one or more independently selected from R^xa, oxygen Dai Ji, halogeno-group ,-NO₂、-N(R^v)₂、-CN、-C(O)-N(R^v)₂、-S(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-O-R^v、-S- R^v、-O-C(O)-R^v、-C(O)-R^v、-C(O)-O-R^v、-S(O)-R^v、-S(O)₂-R^v、-C(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、- N(R^v)-C(O)-R^v、N(R^v)-C(O)-OR^v、-N(R^v)-S(O)-R^v、-N(R^v)-S(O)₂-R^vAnd C_1-6The group of alkyl is optional Ground replaces, described C_1-6Alkyl is optionally replaced by one or more groups independently selected from oxo base and halogeno-group.

55. compound as according to any one of claim 33 to 40, wherein R³For by oxo base, C_1-6Alkyl, C_2-6Thiazolinyl, C_2-6Alkynyl, carbocylic radical, aryl, heteroaryl, heterocycle ,-F ,-Cl ,-Br ,-I ,-NO₂、-N(R^v)₂、-CN、-C(O)-N(R^v)₂、-S (O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-O-R^v、-S-R^v、-O-C(O)-R^v、-O-C(O)-O-R^v、-C(O)-R^v、-C(O)-O- R^v、-S(O)-R^v、-S(O)₂-R^v、-O-C(O)-N(R^v)₂、-N(R^v)-C(O)-OR^v、-N(R^v)-C(O)-N(R^v)₂、-S(O)₂-N (R^v)₂、-N(R^v)-C(O)-R^v、-N(R^v)-S(O)-R^v、-N(R^v)-S(O)₂-R^v、-N(R^v)-S(O)-N(R^v)₂Or-N (R^v)-S (O)₂-N(R^v)₂Substituted heteroaryl；Any of which C_1–6Alkyl by one or more independently selected from R^xa, oxo base, halo Base ,-NO₂、-N(R^v)₂、-CN、-C(O)-N(R^v)₂、-S(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-O-R^v、-S-R^v、-O-C(O)- R^v、-C(O)-R^v、-C(O)-O-R^v、-S(O)-R^v、-S(O)₂-R^v、-C(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-N(R^v)-C(O)- R^v、-N(R^v)-C(O)-OR^v、-N(R^v)-S(O)-R^vAnd-N (R^v)-S(O)₂-R^v；And any of which C_2-6Thiazolinyl, C_2–6Alkynes Base, carbocylic radical, aryl, heteroaryl and heterocyclic radical by one or more independently selected from R^xa, oxo base, halogeno-group ,-NO₂、-N (R^v)₂、-CN、-C(O)-N(R^v)₂、-S(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-O-R^v、-S-R^v、-O-C(O)-R^v、-C(O)- R^v、-C(O)-O-R^v、-S(O)-R^v、-S(O)₂-R^v、-C(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-N(R^v)-C(O)-R^v、-N (R^v)-C(O)-OR^v、-N(R^v)-S(O)-R^v、-N(R^v)-S(O)₂-R^vAnd C_1-6The group of alkyl optionally replaces, described C_1-6 Alkyl is optionally replaced by one or more groups independently selected from oxo base and halogeno-group.

56. compound as according to any one of claim 33 to 40, wherein R³For by oxo base, C_1-6Alkyl, C_2-6Thiazolinyl, C_2-6Alkynyl, carbocylic radical, aryl, heteroaryl, heterocycle ,-F ,-Cl ,-Br ,-I ,-NO₂、-N(R^v)₂、-CN、-C(O)-N(R^v)₂、-S (O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-O-R^v、-S-R^v、-O-C(O)-R^v、-O-C(O)-O-R^v、-C(O)-R^v、-C(O)-O- R^v、-S(O)-R^v、-S(O)₂-R^v、-O-C(O)-N(R^v)₂、-N(R^v)-C(O)-OR^v、-N(R^v)-C(O)-N(R^v)₂、-S(O)₂-N (R^v)₂、-N(R^v)-C(O)-R^v、-N(R^v)-S(O)-R^v、-N(R^v)-S(O)₂-R^v、-N(R^v)-S(O)-N(R^v)₂Or-N (R^v)-S (O)₂-N(R^v)₂Substituted 5 yuan of heteroaryls；Any of which C_1-6Alkyl by one or more independently selected from R^xa, oxo base, halogen Dai Ji ,-NO₂、-N(R^v)₂、-CN、-C(O)-N(R^v)₂、-S(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-O-R^v、-S-R^v、-O-C (O)-R^v、-C(O)-R^v、-C(O)-O-R^v、-S(O)-R^v、-S(O)₂-R^v、-C(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-N(R^v)-C (O)-R^v、-N(R^v)-C(O)-OR^v、-N(R^v)-S(O)-R^vWith-N (R^v)-S(O)₂-R^vGroup optionally replace；And wherein Arbitrary C_2-6Thiazolinyl, C_2–6Alkynyl, carbocylic radical, aryl, heteroaryl and heterocyclic radical by one or more independently selected from R^xa, oxo Base, halogeno-group ,-NO₂、-N(R^v)₂、-CN、-C(O)-N(R^v)₂、-S(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-O-R^v、-S-R^v、- O-C(O)-R^v、-C(O)-R^v、-C(O)-O-R^v、-S(O)-R^v、-S(O)₂-R^v、-C(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-N (R^v)-C(O)-R^v、-N(R^v)-C(O)-OR^v、-N(R^v)-S(O)-R^v、-N(R^v)-S(O)₂-R^vAnd C_1-6The group of alkyl is optional Ground replaces, described C_1-6Alkyl is optionally replaced by one or more groups independently selected from oxo base and halogeno-group.

57. compound as according to any one of claim 33 to 40, wherein R³For by oxo base, C_1-6Alkyl, C_2-6Thiazolinyl, C_2-6Alkynyl, carbocylic radical, aryl, heteroaryl, heterocycle ,-N (R^v)₂、-CN、-C(O)-N(R^v)₂、-S(O)-N(R^v)₂、-S(O)₂-N (R^v)₂、-O-R^v、-S-R^v、-O-C(O)-R^v、-O-C(O)-O-R^v、-C(O)-R^v、-C(O)-O-R^v、-S(O)-R^v、-S(O)₂- R^v、-O-C(O)-N(R^v)₂、-N(R^v)-C(O)-OR^v、-N(R^v)-C(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-N(R^v)-C(O)- R^v、-N(R^v)-S(O)-R^v、-N(R^v)-S(O)₂-R^v、-N(R^v)-S(O)-N(R^v)₂Or-N (R^v)-S(O)₂-N(R^v)₂Substituted benzene Base；Any of which C_1-6Alkyl by one or more independently selected from R^xa, oxo base, halogeno-group ,-NO₂、-N(R^v)₂、-CN、-C (O)-N(R^v)₂、-S(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-O-R^v、-S-R^v、-O-C(O)-R^v、-C(O)-R^v、-C(O)-O- R^v、-S(O)-R^v、-S(O)₂-R^v、-C(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-N(R^v)-C(O)-R^v、-N(R^v)-C(O)-OR^v、- N(R^v)-S(O)-R^vWith-N (R^v)-S(O)₂-R^vGroup optionally replace；And any of which C_2-6Thiazolinyl, C_2-6Alkynyl, carbon Ring group, aryl, heteroaryl and heterocyclic radical by one or more independently selected from R^xa, oxo base, halogeno-group ,-NO₂、-N(R^v)₂、- CN、-C(O)-N(R^v)₂、-S(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-O-R^v、-S-R^v、-O-C(O)-R^v、-C(O)-R^v、-C(O)- O-R^v、-S(O)-R^v、-S(O)₂-R^v、-C(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-N(R^v)-C(O)-R^v、-N(R^v)-C(O)- OR^v、-N(R^v)-S(O)-R^v、-N(R^v)-S(O)₂-R^vAnd C_1-6The group of alkyl optionally replaces, described C_1-6Alkyl is by one Or the multiple group independently selected from oxo base and halogeno-group optionally replaces.

58. compound as according to any one of claim 33 to 36, wherein R²And R³Formed together with the atom being connected with them By one or more R^xThe optionally substituted cyclohexyl ring of group.

59. compound as according to any one of claim 33 to 36, wherein R²And R³Formed together with the atom being connected with them By one or more R^xThe optionally substituted benzyl ring of group.

60. compound as according to any one of claim 33 to 56, wherein R⁴For H, methyl, ethyl, propyl group, cyclopropyl first Base, 2-hydroxyethyl, 2-(dimethylamino) ethyl, phenyl, benzyl or 2-methoxy ethyl.

61. compound as according to any one of claim 33 to 41, wherein R⁴And R³Formed together with the atom being connected with them Heterocyclic radical.

62. 1 kinds of formula (I) compound or its salts described as any one of embodiment 1-432.

63. 1 kinds of formula (I) compound or its salts described as any one of embodiment 1-457.

64. 1 kinds of compositionss, its contained I:

Or its pharmaceutically acceptable salt, wherein:

R¹For-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O) C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N (R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂、- C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；

Each R independently be hydrogen or the optionally substituted group selected from the following: C_1-6Aliphatic series, phenyl, 3-7 unit saturated or Part unsaturated carbocyclic, 8-10 unit dicyclo be saturated, part unsaturated or aromatic ring, has 1-3 independently selected from nitrogen, oxygen or sulfur Heteroatomic 5-6 unit monocycle hetero-aromatic ring, there is 1-2 the saturated or part of heteroatomic 4-7 unit independently selected from nitrogen, oxygen or sulfur Undersaturated heterocycle, there is 1-4 independently selected from the heteroatomic 7-10 unit dicyclo of nitrogen, oxygen or sulfur is saturated or part is unsaturated Heterocycle or there is 1-4 the heteroatomic 8-10 unit Bicyclic heteroaromatic rings independently selected from nitrogen, oxygen or sulfur；

Each R ' independently be-R ,-C (O) R ,-CO₂Shape together with R or two R ' on same nitrogen and the atom between them Become to have 1-2 the heteroatomic 4-7 unit heterocycle independently selected from nitrogen, oxygen and sulfur；

Ring A is

R²And R³Independently be-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C (O)SR、-C(O)C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N (R′)C(O)R、-N(R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R′))N(R′)₂,-C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R2 and R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 0-4 The unsaturated ring of 5-7 unit part of atom or aromatic condensed ring；

R^2′For-R ,-OR ,-SR ,-N (R ')₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O)C(O)R、-C(O) CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N(R′)C(O)N (R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂,-C=NN (R′)₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R^2′And R³Formed together with the atom between them and optionally substituted there is 1-4 independently selected from nitrogen, oxygen and sulfur The unsaturated ring of heteroatomic 5-7 unit part or aromatic condensed ring；

X is-N (R⁴)-,-O-or-S-；

R⁴For-R ,-C (O) R ,-CO₂R or-S (O)₂R；Or:

R⁴And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 1-4 The 5-7 unit of atom is saturated, part is unsaturated or aromatic condensed ring；

R⁵For R ,-C (O) R ,-CO₂R、-C(O)N(R′)₂,-C (O) C (O) R or-C (O) CH₂C(O)R；Or:

R⁵And R²Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 1-4 The 5-7 unit part unsaturation of atom or aromatic condensed ring；And

R⁶For-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O) C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N (R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂、- C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R⁶And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 0-4 The 5-7 unit part unsaturation of atom or aromatic condensed ring；Or

Compound described as any one of claim 1 to 63 or its pharmaceutically acceptable compound,

And pharmaceutically acceptable adjuvant, carrier or excipient.

65. compositionss according to claim 64, itself and combination with other therapeutic agents.

66. compositionss according to claim 65, wherein said other therapeutic agents is chemotherapeutant.

67. 1 kinds for suppressing 2-oxoglutaric acid dependent form enzyme or the method for its mutant activity, described method in biological sample Including by described biological sample and compound of formula I:

Or the step of its salt contact, wherein:

R¹For-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O) C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N (R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂、- C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；

Each R independently be hydrogen or the optionally substituted group selected from the following: C_1-6Aliphatic series, phenyl, 3-7 unit saturated or Part unsaturated carbocyclic, 8-10 unit dicyclo be saturated, part unsaturated or aromatic ring, has 1-3 independently selected from nitrogen, oxygen or sulfur Heteroatomic 5-6 unit list hetero-aromatic ring, have that 1-2 is saturated independently selected from the heteroatomic 4-7 unit of nitrogen, oxygen or sulfur or part the most not Saturated heterocycle, the heteroatomic 7-10 unit dicyclo independently selected from nitrogen, oxygen or sulfur is saturated or part is undersaturated to have 1-4 Heterocycle or there is 1-4 the heteroatomic 8-10 unit Bicyclic heteroaromatic rings independently selected from nitrogen, oxygen or sulfur；

Each R ' independently be-R ,-C (O) R ,-CO₂Shape together with R or two R ' on same nitrogen and the atom between them Become to have 1-2 the heteroatomic 4-7 unit heterocycle independently selected from nitrogen, oxygen and sulfur；

Ring A is

R²And R³Independently be-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C (O)SR、-C(O)C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N (R′)C(O)R、-N(R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R′))N(R′)₂,-C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R²And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 0-4 The unsaturated ring of 5-7 unit part of atom or aromatic condensed ring；

R^2′For-R ,-OR ,-SR ,-N (R ')₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O)C(O)R、-C(O) CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N(R′)C(O)N (R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂,-C=NN (R′)₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R^2′And R³Formed together with the atom between them and optionally substituted there is 1-4 independently selected from nitrogen, oxygen and sulfur The unsaturated ring of heteroatomic 5-7 unit part or aromatic condensed ring；

X is-N (R⁴)-,-O-or-S-；

R⁴For-R ,-C (O) R ,-CO₂R or-S (O)₂R；Or:

R⁴And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 1-4 The 5-7 unit of atom is saturated, part is unsaturated or aromatic condensed ring；

R⁵For R ,-C (O) R ,-CO₂R、-C(O)N(R′)₂,-C (O) C (O) R or-C (O) CH₂C(O)R；Or:

R⁵And R²Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 1-4 The unsaturated ring of 5-7 unit part of atom or aromatic condensed ring；And

R⁶For-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O) C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N (R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂、- C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R⁶And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 0-4 The 5-7 unit part unsaturation of atom or aromatic condensed ring；Or

The step contacted with compound or its salt described as any one of claim 1-63.

68. methods as described in claim 67, wherein said 2-oxoglutaric acid dependent form enzyme is containing Jumonji domain Protein.

69. methods as recited in claim 68, the wherein said protein containing Jumonji domain is that JMJD2 subtribe becomes Member.

70. methods as described in claim 69, wherein said JMJD2 subtribe member is GASC1.

The method of the activity of 71. 1 kinds of 2-oxoglutaric acid dependent form enzymes enlivened in patients for suppression or its mutant, its Compound of formula I is used including to described patient:

Or the step of its pharmaceutically acceptable salt, wherein:

R¹For-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O) C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N (R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂、- C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；

Each R independently be hydrogen or the optionally substituted group selected from the following: C_1-6Aliphatic series, phenyl, 3-7 unit saturated or Part unsaturated carbocyclic, 8-10 unit dicyclo be saturated, part unsaturated or aromatic ring, has 1-3 independently selected from nitrogen, oxygen or sulfur Heteroatomic 5-6 unit list hetero-aromatic ring, have that 1-2 is saturated independently selected from the heteroatomic 4-7 unit of nitrogen, oxygen or sulfur or part the most not Saturated heterocycle, the heteroatomic 7-10 unit dicyclo independently selected from nitrogen, oxygen or sulfur is saturated or part is undersaturated to have 1-4 Heterocycle or there is 1-4 the heteroatomic 8-10 unit Bicyclic heteroaromatic rings independently selected from nitrogen, oxygen or sulfur；

Each R ' independently be-R ,-C (O) R ,-CO₂Shape together with R or two R ' on same nitrogen and the atom between them Become to have 1-2 the heteroatomic 4-7 unit heterocycle independently selected from nitrogen, oxygen and sulfur；

Ring A is

R²And R³Independently be-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C (O)SR、-C(O)C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N (R′)C(O)R、-N(R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R′))N(R′)₂,-C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R²And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 0-4 The unsaturated ring of 5-7 unit part of atom or aromatic condensed ring；

R^2′For-R ,-OR ,-SR ,-N (R ')₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O)C(O)R、-C(O) CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N(R′)C(O)N (R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂,-C=NN (R′)₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R^2′And R³Formed together with the atom between them and optionally substituted there is 1-4 independently selected from nitrogen, oxygen and sulfur Heteroatomic 5-7 unit part unsaturation or aromatic condensed ring；

X is-N (R⁴)-,-O-or-S-；

R⁴For-R ,-C (O) R ,-CO₂R or-S (O)₂R；Or:

R⁴And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 1-4 The 5-7 unit of atom is saturated, part is unsaturated or aromatic condensed ring；

R⁵For R ,-C (O) R ,-CO₂R、-C(O)N(R′)₂,-C (O) C (O) R or-C (O) CH₂C(O)R；Or:

R⁵And R²Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 1-4 The 5-7 unit part unsaturation of atom or aromatic condensed ring；And

R⁶For-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O) C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N (R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂、- C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R⁶And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 0-4 The unsaturated ring of 5-7 unit part of atom or aromatic condensed ring；Or

The step contacted with the compound as according to any one of claim 1-63 or its pharmaceutically acceptable salt.

72. methods as described in claim 71, wherein said 2-oxoglutaric acid dependent form enzyme is containing Jumonji domain Protein.

73. methods as described in claim 72, the wherein said protein containing Jumonji domain is that JMJD2 subtribe becomes Member.

74. methods as described in claim 73, wherein said JMJD2 subtribe member is GASC1.

The method of 75. 1 kinds of diseases mediated for treatment GASC1 in patient in need, described method includes to described trouble Person uses compound of formula I:

Or the step of its pharmaceutically acceptable salt, wherein:

R¹For-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O) C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N (R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂、- C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；

Each R independently be hydrogen or the optionally substituted group selected from the following: C_1-6Aliphatic series, phenyl, 3-7 unit saturated or The undersaturated carbocyclic ring of part, 8-10 unit dicyclo be saturated, part unsaturated or aromatic ring, has 1-3 independently selected from nitrogen, oxygen or sulfur Heteroatomic 5-6 unit list hetero-aromatic ring, there is 1-2 the saturated or part of heteroatomic 4-7 unit independently selected from nitrogen, oxygen or sulfur Undersaturated heterocycle, there is 1-4 independently selected from the heteroatomic 7-10 unit dicyclo of nitrogen, oxygen or sulfur is saturated or part is unsaturated Heterocycle or there is 1-4 the heteroatomic 8-10 unit Bicyclic heteroaromatic rings independently selected from nitrogen, oxygen or sulfur；

Each R ' independently be-R ,-C (O) R ,-CO₂Shape together with R or two R ' on same nitrogen and the atom between them Become to have 1-2 the heteroatomic 4-7 unit heterocycle independently selected from nitrogen, oxygen and sulfur；

Ring A is

R²And R³Independently be-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C (O)SR、-C(O)C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N (R′)C(O)R、-N(R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R′))N(R′)₂,-C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R²And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 0-4 The unsaturated ring of 5-7 unit part of atom or aromatic condensed ring；

R^2′For-R ,-OR ,-SR ,-N (R ')₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O)C(O)R、-C(O) CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N(R′)C(O)N (R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂,-C=NN (R′)₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R^2′And R³Formed together with the atom between them and optionally substituted there is 1-4 independently selected from nitrogen, oxygen and sulfur The unsaturated ring of heteroatomic 5-7 unit part or aromatic condensed ring；

X is-N (R⁴)-,-O-or-S-；

R⁴For-R ,-C (O) R ,-CO₂R or-S (O)₂R；Or:

R⁴And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 1-4 The 5-7 unit of atom is saturated, part is unsaturated or aromatic condensed ring；

R⁵For R ,-C (O) R ,-CO₂R、-C(O)N(R′)₂,-C (O) C (O) R or-C (O) CH₂C(O)R；Or:

R⁵And R²Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 1-4 The unsaturated ring of 5-7 unit part of atom or aromatic condensed ring；And

R⁶For-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O) C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N (R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂、- C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R⁶And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 0-4 The 5-7 unit part unsaturation of atom or aromatic condensed ring；Or

Compound as according to any one of claim 1 to 63 or its pharmaceutically acceptable salt.

76. according to the method described in claim 75, and wherein said disease is cancer.

77. according to the method described in claim 76, and wherein said cancer is breast carcinoma, esophageal carcinoma, carcinoma of prostate or pulmonary carcinoma.

78. a method for the activity of the JARID family enzyme being active in patient for suppression or its mutant, it includes to institute State patient and use compound of formula I:

Or the step of its pharmaceutically acceptable salt, wherein:

R¹For-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O) C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N (R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂、- C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；

Each R independently be hydrogen or the optionally substituted group selected from the following: C_1-6Aliphatic series, phenyl, 3-7 unit saturated or The undersaturated carbocyclic ring of part, 8-10 unit dicyclo be saturated, part unsaturated or aromatic ring, has 1-3 independently selected from nitrogen, oxygen or sulfur Heteroatomic 5-6 unit list hetero-aromatic ring, there is 1-2 the saturated or part of heteroatomic 4-7 unit independently selected from nitrogen, oxygen or sulfur Undersaturated heterocycle, there is 1-4 independently selected from the heteroatomic 7-10 unit dicyclo of nitrogen, oxygen or sulfur is saturated or part is unsaturated Heterocycle or there is 1-4 the heteroatomic 8-10 unit Bicyclic heteroaromatic rings independently selected from nitrogen, oxygen or sulfur；

Each R ' independently be-R ,-C (O) R ,-CO₂Shape together with R or two R ' on same nitrogen and the atom between them Become to have 1-2 the heteroatomic 4-7 unit heterocycle independently selected from nitrogen, oxygen and sulfur；

Ring A is

R²And R³Independently be-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C (O)SR、-C(O)C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N (R′)C(O)R、-N(R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R′))N(R′)₂,-C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R²And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 0-4 The unsaturated ring of 5-7 unit part of atom or aromatic condensed ring；

R^2′For-R ,-OR ,-SR ,-N (R ')₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O)C(O)R、-C(O) CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N(R′)C(O)N (R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂,-C=NN (R′)₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R^2′And R³Formed together with the atom between them and optionally substituted there is 1-4 independently selected from nitrogen, oxygen and sulfur The unsaturated ring of heteroatomic 5-7 unit part or aromatic condensed ring；

X is-N (R⁴)-,-O-or-S-；

R⁴It is-R ,-C (O) R ,-CO₂R or-S (O)₂R；Or:

R⁴And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 1-4 The 5-7 unit of atom is saturated, part is unsaturated or aromatic condensed ring；

R⁵For R ,-C (O) R ,-CO₂R、-C(O)N(R′)₂,-C (O) C (O) R or-C (O) CH₂C(O)R；Or:

R⁵And R²Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 1-4 The unsaturated ring of 5-7 unit part of atom or aromatic condensed ring；And

R⁶For-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O) C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N (R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂、- C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R⁶And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 0-4 The 5-7 unit part unsaturation of atom or aromatic condensed ring；Or

Compound as according to any one of claim 1-63 or the step of its pharmaceutically acceptable salt.

The method of 79. 1 kinds of diseases mediated for treatment JARID in patient in need, described method includes to described trouble Person uses compound of formula I:

Or the step of its pharmaceutically acceptable salt, wherein:

R¹For-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O) C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N (R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂、- C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；

Each R independently be hydrogen or the optionally substituted group selected from the following: C_1-6Aliphatic series, phenyl, 3-7 unit saturated or The undersaturated carbocyclic ring of part, 8-10 unit dicyclo be saturated, part unsaturated or aromatic ring, has 1-3 independently selected from nitrogen, oxygen or sulfur Heteroatomic 5-6 unit list hetero-aromatic ring, there is 1-2 the saturated or part of heteroatomic 4-7 unit independently selected from nitrogen, oxygen or sulfur Undersaturated heterocycle, there is 1-4 independently selected from the heteroatomic 7-10 unit dicyclo of nitrogen, oxygen or sulfur is saturated or part is unsaturated Heterocycle or there is 1-4 the heteroatomic 8-10 unit Bicyclic heteroaromatic rings independently selected from nitrogen, oxygen or sulfur；

Each R ' independently be-R ,-C (O) R ,-CO₂Shape together with R or two R ' on same nitrogen and the atom between them Become to have 1-2 the heteroatomic 4-7 unit heterocycle independently selected from nitrogen, oxygen and sulfur；

Ring A is

R²And R³Independently be-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C (O)SR、-C(O)C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N (R′)C(O)R、-N(R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R′))N(R′)₂,-C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R²And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 0-4 The unsaturated ring of 5-7 unit part of atom or aromatic condensed ring；

R^2′For-R ,-OR ,-SR ,-N (R ')₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O)C(O)R、-C(O) CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N(R′)C(O)N (R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂,-C=NN (R′)₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R^2′And R³Formed together with the atom between them and optionally substituted there is 1-4 independently selected from nitrogen, oxygen and sulfur The unsaturated ring of heteroatomic 5-7 unit part or aromatic condensed ring；

X is-N (R⁴)-,-O-or-S-；

R⁴For-R ,-C (O) R ,-CO₂R or-S (O)₂R；Or:

R⁴And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 1-4 The 5-7 unit of atom is saturated, part is unsaturated or aromatic condensed ring；

R⁵For R ,-C (O) R ,-CO₂R、-C(O)N(R′)₂,-C (O) C (O) R or-C (O) CH₂C(O)R；Or:

R⁵And R²Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 1-4 The unsaturated ring of 5-7 unit part of atom or aromatic condensed ring；And

R⁶For-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O) C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N (R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂、- C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R⁶And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 0-4 The unsaturated ring of 5-7 unit part of atom or aromatic condensed ring；Or

Compound as according to any one of claim 1 to 63 or its pharmaceutically acceptable salt.

80. according to the method described in claim 79, and wherein said disease is melanoma or breast carcinoma.

81. 1 kinds of increases include the treatment of cancer of cytotoxic agent method of effect in individuality, and it includes executing to described individuality Compound of formula I with (a) effective dose:

Or its pharmaceutically acceptable salt, wherein:

R¹For-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O) C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N (R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂、- C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；

Each R independently be hydrogen or the optionally substituted group selected from the following: C_1-6Aliphatic series, phenyl, 3-7 unit saturated or The undersaturated carbocyclic ring of part, 8-10 unit dicyclo be saturated, part unsaturated or aromatic ring, has 1-3 independently selected from nitrogen, oxygen or sulfur Heteroatomic 5-6 unit list hetero-aromatic ring, there is 1-2 the saturated or part of heteroatomic 4-7 unit independently selected from nitrogen, oxygen or sulfur Undersaturated heterocycle, there is 1-4 independently selected from the heteroatomic 7-10 unit dicyclo of nitrogen, oxygen or sulfur is saturated or part is unsaturated Heterocycle or there is 1-4 the heteroatomic 8-10 unit Bicyclic heteroaromatic rings independently selected from nitrogen, oxygen or sulfur；

Each R ' independently be-R ,-C (O) R ,-CO₂Shape together with R or two R ' on same nitrogen and the atom between them Become to have 1-2 the heteroatomic 4-7 unit heterocycle independently selected from nitrogen, oxygen and sulfur；

Ring A is

R²And R³Independently be-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C (O)SR、-C(O)C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N (R′)C(O)R、-N(R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R′))N(R′)₂,-C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R²And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 0-4 The unsaturated ring of 5-7 unit part of atom or aromatic condensed ring；

R^2′For-R ,-OR ,-SR ,-N (R ')₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O)C(O)R、-C(O) CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N(R′)C(O)N (R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂,-C=NN (R′)₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R^2′And R³Formed together with the atom between them and optionally substituted there is 1-4 independently selected from nitrogen, oxygen and sulfur The unsaturated ring of heteroatomic 5-7 unit part or aromatic condensed ring；

X is-N (R⁴)-,-O-or-S-；

R⁴For-R ,-C (O) R ,-CO₂R or-S (O)₂R；Or:

R⁴And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 1-4 The 5-7 unit of atom is saturated, part is unsaturated or aromatic condensed ring；

R⁵For R ,-C (O) R ,-CO₂R、-C(O)N(R′)₂,-C (O) C (O) R or-C (O) CH₂C(O)R；Or:

R⁵And R²Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 1-4 The unsaturated ring of 5-7 unit part of atom or aromatic condensed ring；And

R⁶For-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O) C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N (R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂、- C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R⁶And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 0-4 The unsaturated ring of 5-7 unit part of atom or aromatic condensed ring；Or

Compound as according to any one of claim 1 to 63 or its pharmaceutically acceptable salt；

(b) the described cytotoxic agent of effective dose.

82. 1 kinds of treatments suffer from the individual method of cancer, and described individuality has the developing immunity to drugs cytotoxic agent of increase Probability, described method includes the compound of formula I using (a) effective dose to described individuality:

Or its pharmaceutically acceptable salt, wherein:

R¹For-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O) C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N (R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂、- C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；

Each R independently be hydrogen or the optionally substituted group selected from the following: C_1-6Aliphatic series, phenyl, 3-7 unit saturated or The undersaturated carbocyclic ring of part, 8-10 unit dicyclo be saturated, part unsaturated or aromatic ring, has 1-3 independently selected from nitrogen, oxygen or sulfur Heteroatomic 5-6 unit list hetero-aromatic ring, there is 1-2 the saturated or part of heteroatomic 4-7 unit independently selected from nitrogen, oxygen or sulfur Undersaturated heterocycle, there is 1-4 independently selected from the heteroatomic 7-10 unit dicyclo of nitrogen, oxygen or sulfur is saturated or part is unsaturated Heterocycle or there is 1-4 the heteroatomic 8-10 unit Bicyclic heteroaromatic rings independently selected from nitrogen, oxygen or sulfur；

Each R ' independently be-R ,-C (O) R ,-CO₂Shape together with R or two R ' on same nitrogen and the atom between them Become to have 1-2 the heteroatomic 4-7 unit heterocycle independently selected from nitrogen, oxygen and sulfur；

Ring A is

R²And R³Independently be-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C (O)SR、-C(O)C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N (R′)C(O)R、-N(R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R′))N(R′)₂,-C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R²And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 0-4 The unsaturated ring of 5-7 unit part of atom or aromatic condensed ring；

R^2′For-R ,-OR ,-SR ,-N (R ')₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O)C(O)R、-C(O) CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N(R′)C(O)N (R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂,-C=NN (R′)₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R^2′And R³Formed together with the atom between them and optionally substituted there is 1-4 independently selected from nitrogen, oxygen and sulfur The unsaturated ring of heteroatomic 5-7 unit part or aromatic condensed ring；

X is-N (R⁴)-,-O-or-S-；

R⁴For-R ,-C (O) R ,-CO₂R or-S (O)₂R；Or:

R⁴And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 1-4 The 5-7 unit of atom is saturated, part is unsaturated or aromatic condensed ring；

R⁵For R ,-C (O) R ,-CO₂R、-C(O)N(R′)₂,-C (O) C (O) R or-C (O) CH₂C(O)R；Or:

R⁵And R²Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 1-4 The unsaturated ring of 5-7 unit part of atom or aromatic condensed ring；And

R⁶For-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O) C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N (R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂、- C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R⁶And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 0-4 The unsaturated ring of 5-7 unit part of atom or aromatic condensed ring；Or

Compound as according to any one of claim 1 to 63 or its pharmaceutically acceptable salt；

(b) the described cytotoxic agent of effective dose.

83. the method treating the cancer of individuality, it compound of formula I including using (a) effective dose to described individuality:

Or its pharmaceutically acceptable salt, wherein:

R¹For-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O) C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N (R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂、- C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；

Each R independently be hydrogen or the optionally substituted group selected from the following: C_1-6Aliphatic series, phenyl, 3-7 unit saturated or The undersaturated carbocyclic ring of part, 8-10 unit dicyclo be saturated, part unsaturated or aromatic ring, has 1-3 independently selected from nitrogen, oxygen or sulfur Heteroatomic 5-6 unit list hetero-aromatic ring, there is 1-2 the saturated or part of heteroatomic 4-7 unit independently selected from nitrogen, oxygen or sulfur Undersaturated heterocycle, there is 1-4 independently selected from the heteroatomic 7-10 unit dicyclo of nitrogen, oxygen or sulfur is saturated or part is unsaturated Heterocycle or there is 1-4 the heteroatomic 8-10 unit Bicyclic heteroaromatic rings independently selected from nitrogen, oxygen or sulfur；

Each R ' independently be-R ,-C (O) R ,-CO₂Shape together with R or two R ' on same nitrogen and the atom between them Become to have 1-2 the heteroatomic 4-7 unit heterocycle independently selected from nitrogen, oxygen and sulfur；

Ring A is

R²And R³Independently be-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C (O)SR、-C(O)C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N (R′)C(O)R、-N(R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R′))N(R′)₂,-C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R²And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 0-4 The unsaturated ring of 5-7 unit part of atom or aromatic condensed ring；

R^2′It is-R ,-OR ,-SR ,-N (R ')₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O)C(O)R、-C(O) CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N(R′)C(O)N (R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂,-C=NN (R′)₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R^2′And R³Formed together with the atom between them and optionally substituted there is 1-4 independently selected from nitrogen, oxygen and sulfur The unsaturated ring of heteroatomic 5-7 unit part or aromatic condensed ring；

X is-N (R⁴)-,-O-or-S-；

R⁴For-R ,-C (O) R ,-CO₂R or-S (O)₂R；Or:

R⁴And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 1-4 The 5-7 unit of atom is saturated, part is unsaturated or aromatic condensed ring；

R⁵For R ,-C (O) R ,-CO₂R、-C(O)N(R′)₂,-C (O) C (O) R or-C (O) CH₂C(O)R；Or:

R⁵And R²Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 1-4 The unsaturated ring of 5-7 unit part of atom or aromatic condensed ring；And

R⁶For-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O) C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N (R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂、- C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R⁶And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 0-4 The unsaturated ring of 5-7 unit part of atom or aromatic condensed ring；Or

Compound as according to any one of claim 1 to 63 or its pharmaceutically acceptable salt；

(b) cytotoxic agent.

84. methods as described in claim 83, wherein formula (I) compound as according to any one of claim 1 to 63 or Its pharmaceutically acceptable salt and the respective amount of cytotoxic agent can be effectively increased the time of cancer sensitivity and/or delay cell Cytotoxic agent is developed immunity to drugs.

The method that 85. 1 kinds of increases include the treatment of cancer of cytotoxic agent effect in individuality, it includes to described individuality Use the compound of formula I of effective dose:

Or its pharmaceutically acceptable salt, wherein:

R¹For-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O) C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N (R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂、- C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；

Each R independently be hydrogen or the optionally substituted group selected from the following: C_1-6Aliphatic series, phenyl, 3-7 unit saturated or The undersaturated carbocyclic ring of part, 8-10 unit dicyclo be saturated, part unsaturated or aromatic ring, has 1-3 independently selected from nitrogen, oxygen or sulfur Heteroatomic 5-6 unit list hetero-aromatic ring, there is 1-2 the saturated or part of heteroatomic 4-7 unit independently selected from nitrogen, oxygen or sulfur Undersaturated heterocycle, there is 1-4 independently selected from the heteroatomic 7-10 unit dicyclo of nitrogen, oxygen or sulfur is saturated or part is unsaturated Heterocycle or there is 1-4 the heteroatomic 8-10 unit Bicyclic heteroaromatic rings independently selected from nitrogen, oxygen or sulfur；

Each R ' independently be-R ,-C (O) R ,-CO₂Shape together with R or two R ' on same nitrogen and the atom between them Become to have 1-2 the heteroatomic 4-7 unit heterocycle independently selected from nitrogen, oxygen and sulfur；

Ring A is

R²And R³Independently be-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C (O)SR、-C(O)C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N (R′)C(O)R、-N(R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R′))N(R′)₂,-C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R²And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 0-4 The unsaturated ring of 5-7 unit part of atom or aromatic condensed ring；

R^2′For-R ,-OR ,-SR ,-N (R ')₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O)C(O)R、-C(O) CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N(R′)C(O)N (R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂,-C=NN (R′)₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R^2′And R³Formed together with the atom between them and optionally substituted there is 1-4 independently selected from nitrogen, oxygen and sulfur The unsaturated ring of heteroatomic 5-7 unit part or aromatic condensed ring；

X is-N (R⁴)-,-O-or-S-；

R⁴For-R ,-C (O) R ,-CO₂R or-S (O)₂R；Or:

R⁴And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 1-4 The 5-7 unit of atom is saturated, part is unsaturated or aromatic condensed ring；

R⁵For R ,-C (O) R ,-CO₂R、-C(O)N(R′)₂,-C (O) C (O) R or-C (O) CH₂C(O)R；Or:

R⁵And R²Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 1-4 The unsaturated ring of 5-7 unit part of atom or aromatic condensed ring；And

R⁶For-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O) C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N (R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂、- C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R⁶And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 0-4 The unsaturated ring of 5-7 unit part of atom or aromatic condensed ring；Or

Compound as according to any one of claim 1 to 63 or its pharmaceutically acceptable salt.

86. the method treating the cancer of individuality, wherein treatment of cancer includes the Formulas I using (a) effective dose to described individuality Compound:

Or its pharmaceutically acceptable salt, wherein:

R¹For-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O) C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N (R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂、- C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；

Each R independently be hydrogen or the optionally substituted group selected from the following: C_1-6Aliphatic series, phenyl, 3-7 unit saturated or The undersaturated carbocyclic ring of part, 8-10 unit dicyclo be saturated, part unsaturated or aromatic ring, has 1-3 independently selected from nitrogen, oxygen or sulfur Heteroatomic 5-6 unit list hetero-aromatic ring, there is 1-2 the saturated or part of heteroatomic 4-7 unit independently selected from nitrogen, oxygen or sulfur Undersaturated heterocycle, there is 1-4 independently selected from the heteroatomic 7-10 unit dicyclo of nitrogen, oxygen or sulfur is saturated or part is unsaturated Heterocycle or there is 1-4 the heteroatomic 8-10 unit Bicyclic heteroaromatic rings independently selected from nitrogen, oxygen or sulfur；

Each R ' independently be-R ,-C (O) R ,-CO₂Shape together with R or two R ' on same nitrogen and the atom between them Become to have 1-2 the heteroatomic 4-7 unit heterocycle independently selected from nitrogen, oxygen and sulfur；

Ring A is

R²And R³Independently be-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C (O)SR、-C(O)C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N (R′)C(O)R、-N(R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R′))N(R′)₂,-C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R²And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 0-4 The unsaturated ring of 5-7 unit part of atom or aromatic condensed ring；

R^2′For-R ,-OR ,-SR ,-N (R ')₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O)C(O)R、-C(O) CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N(R′)C(O)N (R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂,-C=NN (R′)₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R^2′And R³Formed together with the atom between them and optionally substituted there is 1-4 independently selected from nitrogen, oxygen and sulfur The unsaturated ring of heteroatomic 5-7 unit part or aromatic condensed ring；

X is-N (R⁴)-,-O-or-S-；

R⁴For-R ,-C (O) R ,-CO₂R or-S (O)₂R；Or:

R⁴And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 1-4 The 5-7 unit of atom is saturated, part is unsaturated or aromatic condensed ring；

R⁵For R ,-C (O) R ,-CO₂R、-C(O)N(R′)₂,-C (O) C (O) R or-C (O) CH₂C(O)R；Or:

R⁵And R²Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 1-4 The unsaturated ring of 5-7 unit part of atom or aromatic condensed ring；And

R⁶For-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O) C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N (R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂、- C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R⁶And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 0-4 The unsaturated ring of 5-7 unit part of atom or aromatic condensed ring；Or

Compound as according to any one of claim 1-63 or its pharmaceutically acceptable salt；And

(b) cytotoxic agent, wherein said treatment of cancer with include using do not have (lacking) described compound or its pharmaceutically may be used The effect with increase is compared in the standard care of the described cytotoxic agent of the effective dose of the salt accepted.

87. 1 kinds delay and/or prevent the method that in individuality, cytotoxic agent is developed immunity to drugs by cancer, and it includes to described Body uses the compound of formula I of effective dose:

Or its pharmaceutically acceptable salt, wherein:

R¹For-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O) C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N (R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂、- C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；

Each R independently be hydrogen or the optionally substituted group selected from the following: C_1-6Aliphatic series, phenyl, 3-7 unit saturated or The undersaturated carbocyclic ring of part, 8-10 unit dicyclo be saturated, part unsaturated or aromatic ring, has 1-3 independently selected from nitrogen, oxygen or sulfur Heteroatomic 5-6 unit list hetero-aromatic ring, there is 1-2 the saturated or part of heteroatomic 4-7 unit independently selected from nitrogen, oxygen or sulfur Undersaturated heterocycle, there is 1-4 independently selected from the heteroatomic 7-10 unit dicyclo of nitrogen, oxygen or sulfur is saturated or part is unsaturated Heterocycle or there is 1-4 the heteroatomic 8-10 unit Bicyclic heteroaromatic rings independently selected from nitrogen, oxygen or sulfur；

Each R ' independently be-R ,-C (O) R ,-CO₂Shape together with R or two R ' on same nitrogen and the atom between them Become to have 1-2 the heteroatomic 4-7 unit heterocycle independently selected from nitrogen, oxygen and sulfur；

Ring A is

R²And R³Independently be-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C (O)SR、-C(O)C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N (R′)C(O)R、-N(R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R′))N(R′)₂,-C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R²And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 0-4 The unsaturated ring of 5-7 unit part of atom or aromatic condensed ring；

R^2′For-R ,-OR ,-SR ,-N (R ')₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O)C(O)R、-C(O) CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N(R′)C(O)N (R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂,-C=NN (R′)₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R^2′And R³Formed together with the atom between them and optionally substituted there is 1-4 independently selected from nitrogen, oxygen and sulfur The unsaturated ring of heteroatomic 5-7 unit part or aromatic condensed ring；

X is-N (R⁴)-,-O-or-S-；

R⁴For-R ,-C (O) R ,-CO₂R or-S (O)₂R；Or:

R⁴And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 1-4 The 5-7 unit of atom is saturated, part is unsaturated or aromatic condensed ring；

R⁵For R ,-C (O) R ,-CO₂R、-C(O)N(R′)₂,-C (O) C (O) R or-C (O) CH₂C(O)R；Or:

R⁵And R²Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 1-4 The unsaturated ring of 5-7 unit part of atom or aromatic condensed ring；And

R⁶For-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O) C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N (R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂、- C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R⁶And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 0-4 The unsaturated ring of 5-7 unit part of atom or aromatic condensed ring；Or

Compound as according to any one of claim 1 to 63 or its pharmaceutically acceptable salt.

88. 1 kinds of treatments suffer from the individual method of cancer, and described individuality has the developing immunity to drugs cytotoxic agent of increase Probability, described method includes the compound of formula I using (a) effective dose to described individuality:

Or its pharmaceutically acceptable salt, wherein:

R¹For-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O) C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N (R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂、- C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；

Each R independently be hydrogen or the optionally substituted group selected from the following: C_1-6Aliphatic series, phenyl, 3-7 unit saturated or The undersaturated carbocyclic ring of part, 8-10 unit dicyclo be saturated, part unsaturated or aromatic ring, has 1-3 independently selected from nitrogen, oxygen or sulfur Heteroatomic 5-6 unit list hetero-aromatic ring, there is 1-2 the saturated or part of heteroatomic 4-7 unit independently selected from nitrogen, oxygen or sulfur Undersaturated heterocycle, there is 1-4 independently selected from the heteroatomic 7-10 unit dicyclo of nitrogen, oxygen or sulfur is saturated or part is unsaturated Heterocycle or there is 1-4 the heteroatomic 8-10 unit Bicyclic heteroaromatic rings independently selected from nitrogen, oxygen or sulfur；

Each R ' independently be-R ,-C (O) R ,-CO₂Shape together with R or two R ' on same nitrogen and the atom between them Become to have 1-2 the heteroatomic 4-7 unit heterocycle independently selected from nitrogen, oxygen and sulfur；

Ring A is

R²And R³Independently be-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C (O)SR、-C(O)C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N (R′)C(O)R、-N(R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R′))N(R′)₂,-C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R²And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 0-4 The unsaturated ring of 5-7 unit part of atom or aromatic condensed ring；

R^2′It is-R ,-OR ,-SR ,-N (R ')₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O)C(O)R、-C(O) CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N(R′)C(O)N (R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂,-C=NN (R′)₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R^2′And R³Formed together with the atom between them and optionally substituted there is 1-4 independently selected from nitrogen, oxygen and sulfur The unsaturated ring of heteroatomic 5-7 unit part or aromatic condensed ring；

X is-N (R⁴)-,-O-or-S-；

R⁴For-R ,-C (O) R ,-CO₂R or-S (O)₂R；Or:

R⁴And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 1-4 The 5-7 unit of atom is saturated, part is unsaturated or aromatic condensed ring；

R⁵For R ,-C (O) R ,-CO₂R、-C(O)N(R′)₂,-C (O) C (O) R or-C (O) CH₂C(O)R；Or:

R⁵And R²Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 1-4 The unsaturated ring of 5-7 unit part of atom or aromatic condensed ring；And

R⁶For-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O) C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N (R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂、- C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R⁶And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 0-4 The unsaturated ring of 5-7 unit part of atom or aromatic condensed ring；Or

Compound as according to any one of claim 1 to 63 or its pharmaceutically acceptable salt；And

The described cytotoxic agent of (b) effective dose.

The method that 89. 1 kinds of increases suffer from the individual sensitivity to cytotoxic agent of cancer, it includes having used to described individuality The compound of formula I of effect amount:

Or its pharmaceutically acceptable salt, wherein:

R¹For-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O) C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N (R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂、- C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；

Each R independently be hydrogen or the optionally substituted group selected from the following: C_1-6Aliphatic series, phenyl, 3-7 unit saturated or The undersaturated carbocyclic ring of part, 8-10 unit dicyclo be saturated, part unsaturated or aromatic ring, has 1-3 independently selected from nitrogen, oxygen or sulfur Heteroatomic 5-6 unit list hetero-aromatic ring, there is 1-2 the saturated or part of heteroatomic 4-7 unit independently selected from nitrogen, oxygen or sulfur Undersaturated heterocycle, there is 1-4 independently selected from the heteroatomic 7-10 unit dicyclo of nitrogen, oxygen or sulfur is saturated or part is unsaturated Heterocycle or there is 1-4 the heteroatomic 8-10 unit Bicyclic heteroaromatic rings independently selected from nitrogen, oxygen or sulfur；

Each R ' independently be-R ,-C (O) R ,-CO₂Shape together with R or two R ' on same nitrogen and the atom between them Become to have 1-2 the heteroatomic 4-7 unit heterocycle independently selected from nitrogen, oxygen and sulfur；

Ring A is

R²And R³Independently be-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C (O)SR、-C(O)C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N (R′)C(O)R、-N(R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R′))N(R′)₂,-C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R²And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 0-4 The unsaturated ring of 5-7 unit part of atom or aromatic condensed ring；

R^2′It is-R ,-OR ,-SR ,-N (R ')₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O)C(O)R、-C(O) CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N(R′)C(O)N (R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂,-C=NN (R′)₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R^2′And R³Formed together with the atom between them and optionally substituted there is 1-4 independently selected from nitrogen, oxygen and sulfur The unsaturated ring of heteroatomic 5-7 unit part or aromatic condensed ring；

X is-N (R⁴)-,-O-or-S-；

R⁴For-R ,-C (O) R ,-CO₂R or-S (O)₂R；Or:

R⁴And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 1-4 The 5-7 unit of atom is saturated, part is unsaturated or aromatic condensed ring；

R⁵For R ,-C (O) R ,-CO₂R、-C(O)N(R′)₂,-C (O) C (O) R or-C (O) CH₂C(O)R；Or:

R⁵And R²Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 1-4 The unsaturated ring of 5-7 unit part of atom or aromatic condensed ring；And

R⁶For-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O) C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N (R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂、- C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R⁶And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 0-4 The 5-7 unit part unsaturation of atom or aromatic condensed ring；Or

Compound as according to any one of claim 1 to 63 or its pharmaceutically acceptable salt.

90. 1 kinds extend the method for the time of cancer therapeutic agent sensitivity in suffering from cancer individuality, and it includes to described individuality Use the compound of formula I of effective dose:

Or its pharmaceutically acceptable salt, wherein:

R¹For-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O) C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N (R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂、- C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；

Each R independently be hydrogen or the optionally substituted group selected from the following: C_1-6Aliphatic series, phenyl, 3-7 unit saturated or The undersaturated carbocyclic ring of part, 8-10 unit dicyclo be saturated, part unsaturated or aromatic ring, has 1-3 independently selected from nitrogen, oxygen or sulfur Heteroatomic 5-6 unit list hetero-aromatic ring, there is 1-2 the saturated or part of heteroatomic 4-7 unit independently selected from nitrogen, oxygen or sulfur Undersaturated heterocycle, there is 1-4 independently selected from the heteroatomic 7-10 unit dicyclo of nitrogen, oxygen or sulfur is saturated or part is unsaturated Heterocycle or there is 1-4 the heteroatomic 8-10 unit Bicyclic heteroaromatic rings independently selected from nitrogen, oxygen or sulfur；

Each R ' independently be-R ,-C (O) R ,-CO₂Shape together with R or two R ' on same nitrogen and the atom between them Become to have 1-2 the heteroatomic 4-7 unit heterocycle independently selected from nitrogen, oxygen and sulfur；

Ring A is

R²And R³Independently be-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C (O)SR、-C(O)C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N (R′)C(O)R、-N(R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R′))N(R′)₂,-C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R²And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 0-4 The unsaturated ring of 5-7 unit part of atom or aromatic condensed ring；

R^2′For-R ,-OR ,-SR ,-N (R ')₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O)C(O)R、-C(O) CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N(R′)C(O)N (R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂,-C=NN (R′)₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R^2′And R³Formed together with the atom between them and optionally substituted there is 1-4 independently selected from nitrogen, oxygen and sulfur Heteroatomic 5-7 unit part unsaturation or aromatic condensed ring；

X is-N (R⁴)-,-O-or-S-；

R⁴For-R ,-C (O) R ,-CO₂R or-S (O)₂R；Or:

R⁴And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 1-4 The 5-7 unit of atom is saturated, part is unsaturated or aromatic condensed ring；

R⁵For R ,-C (O) R ,-CO₂R、-C(O)N(R′)₂,-C (O) C (O) R or-C (O) CH₂C(O)R；Or:

R⁵And R²Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 1-4 The unsaturated ring of 5-7 unit part of atom or aromatic condensed ring；And

R⁶For-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O) C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N (R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂、- C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R⁶And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 0-4 The unsaturated ring of 5-7 unit part of atom or aromatic condensed ring；Or

Compound as according to any one of claim 1 to 63 or its pharmaceutically acceptable salt.

91. 1 kinds of prolongations suffer from the individuality of the cancer method to the persistent period of the response for the treatment of of cancer, and it includes to described Body uses the compound of formula I of effective dose:

Or its pharmaceutically acceptable salt, wherein:

R¹For-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O) C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N (R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂、- C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；

Each R independently be hydrogen or the optionally substituted group selected from the following: C_1-6Aliphatic series, phenyl, 3-7 unit saturated or The undersaturated carbocyclic ring of part, 8-10 unit dicyclo be saturated, part unsaturated or aromatic ring, has 1-3 independently selected from nitrogen, oxygen or sulfur Heteroatomic 5-6 unit list hetero-aromatic ring, there is 1-2 the saturated or part of heteroatomic 4-7 unit independently selected from nitrogen, oxygen or sulfur Undersaturated heterocycle, there is 1-4 independently selected from the heteroatomic 7-10 unit dicyclo of nitrogen, oxygen or sulfur is saturated or part is unsaturated Heterocycle or there is 1-4 the heteroatomic 8-10 unit Bicyclic heteroaromatic rings independently selected from nitrogen, oxygen or sulfur；

Each R ' independently be-R ,-C (O) R ,-CO₂Shape together with R or two R ' on same nitrogen and the atom between them Become to have 1-2 the heteroatomic 4-7 unit heterocycle independently selected from nitrogen, oxygen and sulfur；

Ring A is

R²And R³Independently be-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C (O)SR、-C(O)C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N (R′)C(O)R、-N(R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R′))N(R′)₂,-C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R²And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 0-4 The unsaturated ring of 5-7 unit part of atom or aromatic condensed ring；

R^2′For-R ,-OR ,-SR ,-N (R ')₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O)C(O)R、-C(O) CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N(R′)C(O)N (R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂,-C=NN (R′)₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R^2′And R³Formed together with the atom between them and optionally substituted there is 1-4 independently selected from nitrogen, oxygen and sulfur The unsaturated ring of heteroatomic 5-7 unit part or aromatic condensed ring；

X is-N (R⁴)-,-O-or-S-；

R⁴For-R ,-C (O) R ,-CO₂R or-S (O)₂R；Or:

R⁴And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 1-4 The 5-7 unit of atom is saturated, part is unsaturated or aromatic condensed ring；

R⁵For R ,-C (O) R ,-CO₂R、-C(O)N(R′)₂,-C (O) C (O) R or-C (O) CH₂C(O)R；Or:

R⁵And R²Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 1-4 The unsaturated ring of 5-7 unit part of atom or aromatic condensed ring；And

R⁶For-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O) C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N (R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂、- C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R⁶And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 0-4 The unsaturated ring of 5-7 unit part of atom or aromatic condensed ring；Or

Compound as according to any one of claim 1 to 63 or its pharmaceutically acceptable salt.

92. methods as according to any one of claim 84,85,87 and 89, wherein said method also includes that (b) is to described Body uses the described cytotoxic agent of effective dose.

93. methods as according to any one of claim 81 to 92, wherein said cytotoxic agent is chemotherapeutant.

94. methods as described in claim 93, wherein said chemotherapeutant is taxane.

95. methods as described in claim 94, wherein said taxanes is paclitaxel or docetaxel.

96. methods as described in claim 93, wherein said chemotherapeutant is platinum class medicament.

97. methods as according to any one of claim 81 to 92, wherein said cytotoxic agent is selected from: anti-micro-pipe agent, platinum Co-ordination complex, alkylating agent, antibiotic agent, Topoisomerase II inhibitors, antimetabolite, topoisomerase I inhibitor, hormone With hormone analogs, signal transduction pathway inhibitor, nonreceptor tyrosine kinase angiogenesis inhibitor, immunotherapeutic agent, rush Apoptosis agent, LDH-A inhibitor；Fatty acid biological synthetic inhibitor；Cell cycle signals conduction depressant drug, HDAC suppress Agent, proteasome inhibitor；And cancer metabolic poison.

98. methods as described in claim 93, wherein said chemotherapeutant is EGFR antagonist.

99. methods as described in claim 98, wherein said EGFR antagonist is N-(3-ethynyl phenyl)-6, the double (2-of 7- Methoxy ethoxy) quinazoline-4-amine or its pharmaceutically acceptable salt.

100. methods as described in claim 93, wherein said chemotherapeutant is RAF inhibitor.

101. methods as described in claim 100, wherein said RAF inhibitor is BRAF and/or CRAF inhibitor.

102. methods as described in claim 100, wherein said RAF inhibitor is Wei Luofeini.

103. methods as described in claim 93, wherein said chemotherapeutant is PI3K inhibitor.

The method of 104. 1 kinds of proliferative disorders treated in individuality, it Formulas I chemical combination including using effective dose to described individuality Thing:

Or its pharmaceutically acceptable salt, wherein:

R¹For-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O) C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N (R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂、- C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；

Each R independently be hydrogen or the optionally substituted group selected from the following: C_1-6Aliphatic series, phenyl, 3-7 unit saturated or The undersaturated carbocyclic ring of part, 8-10 unit dicyclo be saturated, part unsaturated or aromatic ring, has 1-3 independently selected from nitrogen, oxygen or sulfur Heteroatomic 5-6 unit list hetero-aromatic ring, there is 1-2 the saturated or part of heteroatomic 4-7 unit independently selected from nitrogen, oxygen or sulfur Undersaturated heterocycle, there is 1-4 independently selected from the heteroatomic 7-10 unit dicyclo of nitrogen, oxygen or sulfur is saturated or part is unsaturated Heterocycle or there is 1-4 the heteroatomic 8-10 unit Bicyclic heteroaromatic rings independently selected from nitrogen, oxygen or sulfur；

Each R ' independently be-R ,-C (O) R ,-CO₂Shape together with R or two R ' on same nitrogen and the atom between them Become to have 1-2 the heteroatomic 4-7 unit heterocycle independently selected from nitrogen, oxygen and sulfur；

Ring A is

R²And R³Independently be-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C (O)SR、-C(O)C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N (R′)C(O)R、-N(R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R′))N(R′)₂,-C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R²And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 0-4 The unsaturated ring of 5-7 unit part of atom or aromatic condensed ring；

R^2′For-R ,-OR ,-SR ,-N (R ')₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O)C(O)R、-C(O) CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N(R′)C(O)N (R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂,-C=NN (R′)₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R^2′And R³Formed together with the atom between them and optionally substituted there is 1-4 independently selected from nitrogen, oxygen and sulfur The unsaturated ring of heteroatomic 5-7 unit part or aromatic condensed ring；

X is-N (R⁴)-,-O-or-S-；

R⁴For-R ,-C (O) R ,-CO₂R or-S (O)₂R；Or:

R⁴And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 1-4 The 5-7 unit of atom is saturated, part is unsaturated or aromatic condensed ring；

R⁵For R ,-C (O) R ,-CO₂R、-C(O)N(R′)₂,-C (O) C (O) R or-C (O) CH₂C(O)R；Or:

R⁵And R²Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 1-4 The unsaturated ring of 5-7 unit part of atom or aromatic condensed ring；And

R⁶For-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O) C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N (R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂、- C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R⁶And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 0-4 The unsaturated ring of 5-7 unit part of atom or aromatic condensed ring；Or

Compound as according to any one of claim 1 to 63 or its pharmaceutically acceptable salt.

105. methods as described in claim 104, wherein said proliferative disorders be pulmonary carcinoma, melanoma, colorectal carcinoma, Cancer of pancreas and/or breast carcinoma.

106. 1 kinds of compound of formula I:

Or its pharmaceutically acceptable salt, wherein:

R¹For-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O) C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N (R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂、- C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；

Each R independently be hydrogen or the optionally substituted group selected from the following: C_1-6Aliphatic series, phenyl, 3-7 unit saturated or The undersaturated carbocyclic ring of part, 8-10 unit dicyclo be saturated, part unsaturated or aromatic ring, has 1-3 independently selected from nitrogen, oxygen or sulfur Heteroatomic 5-6 unit list hetero-aromatic ring, there is 1-2 the saturated or part of heteroatomic 4-7 unit independently selected from nitrogen, oxygen or sulfur Undersaturated heterocycle, there is 1-4 independently selected from the heteroatomic 7-10 unit dicyclo of nitrogen, oxygen or sulfur is saturated or part is unsaturated Heterocycle or there is 1-4 the heteroatomic 8-10 unit Bicyclic heteroaromatic rings independently selected from nitrogen, oxygen or sulfur；

Each R ' independently be-R ,-C (O) R ,-CO₂Shape together with R or two R ' on same nitrogen and the atom between them Become to have 1-2 the heteroatomic 4-7 unit heterocycle independently selected from nitrogen, oxygen and sulfur；

Ring A is

R²And R³Independently be-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C (O)SR、-C(O)C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N (R′)C(O)R、-N(R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R′))N(R′)₂,-C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R²And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 0-4 The unsaturated ring of 5-7 unit part of atom or aromatic condensed ring；

R^2′For-R ,-OR ,-SR ,-N (R ')₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O)C(O)R、-C(O) CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N(R′)C(O)N (R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂,-C=NN (R′)₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R^2′And R³Formed together with the atom between them and optionally substituted there is 1-4 independently selected from nitrogen, oxygen and sulfur The unsaturated ring of heteroatomic 5-7 unit part or aromatic condensed ring；

X is-N (R⁴)-,-O-or-S-；

R⁴For-R ,-C (O) R ,-CO₂R or-S (O)₂R；Or:

R⁴And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 1-4 The 5-7 unit of atom is saturated, part is unsaturated or aromatic condensed ring；

R⁵For R ,-C (O) R ,-CO₂R、-C(O)N(R′)₂,-C (O) C (O) R or-C (O) CH₂C(O)R；Or:

R⁵And R²Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 1-4 The unsaturated ring of 5-7 unit part of atom or aromatic condensed ring；And

R⁶For-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O) C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N (R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂、- C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R⁶And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 0-4 The 5-7 unit part unsaturation of atom or aromatic condensed ring；Or

Compound as according to any one of claim 1 to 63 or its pharmaceutically acceptable salt；

In therapeutic treatment.

107. 1 kinds of compound of formula I:

Or its pharmaceutically acceptable salt, wherein:

R¹For-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O) C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N (R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂、- C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；

Each R independently be hydrogen or the optionally substituted group selected from the following: C_1-6Aliphatic series, phenyl, 3-7 unit saturated or The undersaturated carbocyclic ring of part, 8-10 unit dicyclo be saturated, part unsaturated or aromatic ring, has 1-3 independently selected from nitrogen, oxygen or sulfur Heteroatomic 5-6 unit list hetero-aromatic ring, there is 1-2 the saturated or part of heteroatomic 4-7 unit independently selected from nitrogen, oxygen or sulfur Undersaturated heterocycle, there is 1-4 independently selected from the heteroatomic 7-10 unit dicyclo of nitrogen, oxygen or sulfur is saturated or part is unsaturated Heterocycle or there is 1-4 the heteroatomic 8-10 unit Bicyclic heteroaromatic rings independently selected from nitrogen, oxygen or sulfur；

Each R ' independently be-R ,-C (O) R ,-CO₂Shape together with R or two R ' on same nitrogen and the atom between them Become to have 1-2 the heteroatomic 4-7 unit heterocycle independently selected from nitrogen, oxygen and sulfur；

Ring A is

R²And R³Independently be-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C (O)SR、-C(O)C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N (R′)C(O)R、-N(R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R′))N(R′)₂,-C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R²And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 0-4 The unsaturated ring of 5-7 unit part of atom or aromatic condensed ring；

R^2′For-R ,-OR ,-SR ,-N (R ')₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O)C(O)R、-C(O) CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N(R′)C(O)N (R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂,-C=NN (R′)₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R^2′And R³Formed together with the atom between them and optionally substituted there is 1-4 independently selected from nitrogen, oxygen and sulfur The unsaturated ring of heteroatomic 5-7 unit part or aromatic condensed ring；

X is-N (R⁴)-,-O-or-S-；

R⁴For-R ,-C (O) R ,-CO₂R or-S (O)₂R；Or:

R⁴And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 1-4 The 5-7 unit of atom is saturated, part is unsaturated or aromatic condensed ring；

R⁵For R ,-C (O) R ,-CO₂R、-C(O)N(R′)₂,-C (O) C (O) R or-C (O) CH₂C(O)R；Or:

R⁵And R²Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 1-4 The unsaturated ring of 5-7 unit part of atom or aromatic condensed ring；And

R⁶For-R, halogen ,-OR ,-SR ,-N (R ')₂、-CN、-NO₂、-C(O)R、-CO₂R、-C(O)N(R′)₂、-C(O)SR、-C(O) C(O)R、-C(O)CH₂C(O)R、-C(S)N(R′)₂、-C(S)OR、-S(O)R、-SO₂R、-SO₂N(R′)₂、-N(R′)C(O)R、-N (R′)C(O)N(R′)₂、-N(R′)SO₂R、-N(R′)SO₂N(R′)₂、-N(R′)N(R′)₂,-N (R ') C (=N (R ')) N (R ')₂、- C=NN (R ')₂,-C=NOR ,-C (=N (R ')) N (R ')₂,-OC (O) R or-OC (O) N (R ')₂；Or:

R⁶And R³Formed together with the atom between them and optionally substituted there is miscellaneous independently selected from nitrogen, oxygen and sulfur of 0-4 The unsaturated ring of 5-7 unit part of atom or aromatic condensed ring；Or

Compound as according to any one of claim 1 to 63 or its pharmaceutically acceptable salt；

For preventative or therapeutic treatment proliferative disorders.